Antiviral ethers of aspartate protease substrate isosteres

ABSTRACT

Antiretroviral compounds (which are effective, for example, against HIV) of the formula I ##STR1## in which R 1  is an acyl radical lower-alkoxy-lower-alkanoyl whose lower alkoxy radical is unsubstituted or is substituted by halogen, phenyl, lower alkoxy or a heterocyclic radical selected from piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolidinyl, thiazolyl, indolyl or 4H-1-benzopyranyl which is unsubstituted or substituted by oxo, hydroxyl, amino, lower alkyl, lower-alkoxycarbonyl and/or phenyl-lower-alkoxycarbonyl; lower alkanoyl which is unsubstituted or is substituted by one of the said unsubstituted or substituted heterocyclic radicals; arylcarbonyl or heterocyclylcarbonyl which are substituted by heterocyclyl or heterocyclyl-lower-alkyl; phenyl-lower-alkanoyl which is substituted by hydroxyl and lower alkyl; or arylsulfonyl; 
     or the residue of an amino acid which is defined in accordance with the description (and which may be acylated on the amino nitrogen by one of the abovementioned acyl radicals); 
     R 2  and R 3  are in each case cyclohexyl, cyclohexenyl, phenyl, naphthyl or tetrahydronaphthyl which are unsubstituted or substituted by lower alkyl, phenyl, cyanophenyl, phenyl-lower-alkyl, halogen, halo-lower-alkyl, cyano, hydroxyl, lower alkoxy, phenyl-lower-alkoxyl, pyridyl-lower-alkoxy, lower-alkoxy-lower-alkoxy, lower-alkoxycarbonyl-lower-alkoxy, carboxyl-lower-alkoxy, hydroxyl-lower-alkoxy, carbamoyl-lower-alkoxy, cyano-lower-alkoxy, and phenyl-lower-alkanesulfonyl which is unsubstituted or substituted by halogen; 
     R 4  is lower alkyl, cyclohexyl or phenyl; and R 5  is lower alkyl; and n is 1 or 2, 
     or salts thereof, are novel.

This is a divisional application of U.S. application Ser. No. 08/838,347filed Apr. 8, 1997, now U.S. Pat. No. 5,807,891 which is a divisional ofU.S. application Ser. No. 08/545,170, filed on Oct. 19, 1995, now U.S.Pat. No. 5,663,200.

RESUME AND FIELD OF THE INVENTION

The invention relates to ethers of aspartate protease substrateisosteres and their salts, to processes for preparing these compoundsand the salts thereof, to pharmaceutical preparations which comprisethese compounds or the salts thereof, and to the use of these compoundsor the salts thereof (either alone or in combination with other activecompounds which are effective against retroviruses) for the therapeuticor diagnostic treatment of the human or animal body or for producingpharmaceutical preparations.

BACKGROUND OF THE INVENTION

According to WHO estimates, considerably more than 15 million people arecurrently infected with HIV-1 or HIV-2.

Inhibitors of reverse transcriptase, an enzyme which converts retroviralRNA into DNA, such as 3'-azido-3'-deoxythymidine (AZT) or dideoxyinosine(DDI), and also trisodium phosphonoformate, ammonium21-tungsto-9-antimoniate,1-β-D-ribofuranoxyl-1,2,4-triazole-3-carboxamide and dideoxycytidine,and also adriamycin, have primarily been used hitherto for treatingretroviral diseases such as AIDS. Attempts are also being made tointroduce the T4 cell receptor, which is present in the human body oncertain cells of the immune system and which is responsible foranchoring infectious viral particles and introducing them into thesecells, and is consequently responsible for their ability to infect, intothe body, for example as a recombinant molecule or molecular fragment.This would have the effect of titrating out binding sites for the virusso that the virions would no longer be able to bind to the cells.Compounds which use other means to prevent the virus penetrating throughthe cell membrane, such as polymannoacetate, are also used.

In addition to this, the first clinical experiments in which ahydroxyethylene isostere, N-tert-butyldecahydro-2-2(R)-hydroxy-4-phenyl-3(S)-N-2-quinolylcarbonyl-L-asparaginyl!amino!butyl!-(4aS,8aS)-isoquinoline-3(S)-carboxamide(Ro 31-8959) is used as an inhibitor of the HIV protease have beenreported. This compound had an inhibitory effect on HIV protease invitro and suppressed viral replication in cell experiments, and usefulblood levels were achieved in rodents even with oral administration (seeRoberts, N. A., et al., Biochemical Soc. Transactions 20 513-516(1992)); useful blood levels were also achieved in humans (see, forexample, G. J.

Muirhead et al., Brit. J. Clin. Pharmacol. 34, 170P-171P (1992)). Aso-called "surrogate marker" (titre of the CD4 lymphocytes in the blood,whose decline in untreated patients represents a measure of thedevelopment of the AIDS disease) demonstrated the first positive effectsin AIDS patients (see "Roche statement on HIV Proteinase Inhibitor (Ro31-8959) European Trials Results", which was distributed to participantsat the 9th International Congress on AIDS in Berlin, Jun. 7-11, 1993).

In the AIDS viruses, HIV-1 and HIV-2, and in other retroviruses, forexample the corresponding viruses in cats (FIV) and monkeys (SIV),proteolytic maturation, for example of the core proteins of the virus,is effected by an aspartate protease, such as the HIV protease. Noinfectious viral particles can be produced without this proteolyticmaturation. On the basis of the central role played by the saidaspartate proteases, such as HIV-1 protease or HIV-2 protease, in viralmaturation, and on the basis of experimental results, for exampleobtained with infected cell cultures, it is assumed that effectiveprevention in vivo of the maturation step which is brought about by thisprotease will prevent mature virions from being assembled. Consequently,appropriate inhibitors can be employed therapeutically.

It is the object of the present invention to prepare a novel class ofcompounds which also possess, in particular, favourable pharmacologicalproperties, such as good pharmacokinetics, bioavailability and/or goodtolerability.

DETAILED DESCRIPTION OF THE INVENTION

The novel ethers of aspartate protease substrate isosteres are compoundsof the formula I, ##STR2## in which R₁ is an acyl radical which isselected from lower-alkoxy-lower-alkanoyl (includinglower-alkoxycarbonyl), in which the lower-alkoxy radical isunsubstituted or is substituted by one or more radicals selected,independently of each other, from halogen, phenyl and lower-alkoxy, orby a radical selected from piperidinyl, pyrrolidinyl, tetrahydropyranyl,tetrahydrofuranyl, thiazolidinyl, thiazolyl, indolyl or4H-1-benzopyranyl which are unsubstituted or substituted by one or moreradicals selected, independently of each other, from oxo, hydroxyl,amino, lower alkyl, lower alkoxycarbonyl andphenyl-lower-alkoxycarbonyl; lower alkanoyl which is unsubstituted or issubstituted by piperidinyl, pyrrolidinyl, tetrahydropyranyl,tetrahydrofuranyl, thiazolidinyl, thiazolyl, indolyl, 4H-1-benzopyranyl,piperidinyloxy, pyrrolidinyloxy, tetrahydropyranyloxy,tetrahydrofuranyloxy, thiazolidinyloxy, thiazolyloxy, indolyloxy or4H-1-benzopyranyloxy which are in each case unsubstituted or substitutedby one or more substituents selected, independently of each other, fromoxo, hydroxyl, amino, lower alkyl, lower-alkoxycarbonyl andphenyl-lower-alkoxycarbonyl; arylcarbonyl or heterocyclylcarbonyl whichis substituted by heterocyclyl or heterocyclyl-lower-alkyl;phenyl-lower-alkanoyl which is substituted by hydroxyl and lower alkyl;and arylsulfonyl;

the residue, which is bonded via the carbonyl group, of an amino acidselected from glycine, alanine, 3-aminopropanoic acid, 2-aminobutyricacid, 3-aminobutyric acid, 4-aminobutyric acid, 3-aminopentanoic acid,4-aminopentanoic acid, 5-aminopentanoic acid, 3-aminohexanoic acid,4-aminohexanoic acid, 5-aminohexanoic acid, valine, norvaline, leucine,isoleucine, norleucine, serine, homoserine, threonine, methionine,cysteine, phenylalanine, tyrosine, 4-aminophenylalanine,4-chlorophenylalanine, 4-carboxyphenylalanine, β-phenylserine,phenylglycine, α-naphthylalanine, cyclohexylalanine, cyclohexylglycine,tryptophan, asparatic acid, β-phenyl-lower-alkyl aspartate, asparagine,aminomalonic acid, aminomalonic acid monoamide, glutamic acid,γ-phenyl-lower-alkyl glutamate, glutamine, histidine, arginine, lysine,δ-hydroxylysine, omithine, α,γ-diaminobutyric acid andα,β-diaminopropionic acid;

or the radical, which is bonded via the carbonyl group, of one of thelatter amino acids which is N-acylated on an amino nitrogen by one ofthe previously mentioned acyl radicals,

R₂ and R₃ are, independently of each other, cyclohexyl, cyclohexenyl,phenyl, naphthyl or tetrahydronaphthyl which are unsubstituted or aresubstituted by one or more radicals selected, independently of eachother, from lower alkyl, phenyl, cyanophenyl, phenyl-lower-alkyl,halogen, halo-lower-alkyl, cyano, hydroxyl, lower alkoxy,phenyl-lower-alkoxyl, pyridyl-lower-alkoxy, in which pyridyl is bondedvia a ring carbon atom, lower-alkoxy-lower-alkoxy,lower-alkoxycarbonyl-lower-alkoxy, carboxyl-lower-alkoxy,hydroxyl-lower-alkoxy having at least two carbon atoms, in whichhydroxyl is not bonded in the 1 position, carbamoyl-lower-alkoxy,cyano-lower-alkoxy, lower-alkylenedioxy, and phenyl-lower-alkanesulfonylwhich is unsubstituted or is substituted in the phenyl radical by one ormore radicals selected, independently of each other, from halogen,

R₄ is lower alkyl, cyclohexyl or phenyl, R₅ is lower alkyl, and

n is 1 or 2,

or salts thereof, provided at least one salt-forming group is present.

Within the scope of the present application, the general terms usedabove and below preferably have the following meanings unless otherwiseindicated:

The prefix "lower" or the word component "lower", for example in loweralkyl, lower alkoxy, lower alkanoyl or phenyl-lower-alkyl, denote aradical having not more than 7, in particular not more than 4, carbonatoms, it being possible for the radicals concerned to be unbranched orto be branched once or more than once.

When compounds, salts, etc. are mentioned, these terms also mean acompound, a salt, etc.

Asymmetric carbon atoms which may be present, including those in thesubstituents R₁, R₂, R₃, R₄ and R₅, can be in the (R), (S) or (R,S)configurations, preferably in the (R) configuration or (S)configuration. The present compounds can consequently exist as isomericmixtures or as pure isomers, in particular as diastereomeric mixtures,enantiomeric mixtures or, preferably, pure enantiomers.

The additional statement "alternatively or additionally" means eitherthat the corresponding designated substituent meanings combined with therespective groups of substituent meanings which are not designated withthis additional statement together form a group of substituents, or thatthe correspondingly designated substituent meanings form a group ontheir own, or that the meanings which are not designated with thisadditional statement also on their own form a group of substituentmeanings.

Preferably, the compounds of the formula I have the formula I', ##STR3##in which the radicals have the meanings given for compounds of theformula I.

In lower alkoxy-lower-alkanoyl, R₁ is the lower-alkoxy radical,preferably methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, isobutoxy,sec-butoxy or tert-butoxy, while lower alkanoyl is preferably formyl(the corresponding radical is then a lower-alkoxycarbonyl radical, inparticular methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl),acetyl or propionyl.

Piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl,thiazolidinyl, thiazolyl, indolyl or 4H-1-benzopyranyl are unsubstitutedor substituted by one or more radicals selected, independently of eachother, from oxo, hydroxyl, amino, lower alkyl, lower-alkoxycarbonyl andphenyl-lower-alkoxycarbonyl, in particular unsubstituted or substitutedby one or two of the said radicals selected independently of each other.

Halogen is fluorine, chlorine, bromine or iodine, in particular fluorineor chlorine. Piperidinyl is, in particular, piperidin-4-yl which isunsubstituted or is preferably substituted on the nitrogen atom by loweralkyl, such as methyl, or lower-alkoxycarbonyl, such as ethoxycarbonyl.

Pyrrolidinyl is, in particular, pyrrolidin-2-yl or -5-yl which isunsubstituted or preferably substituted by oxo or hydroxyl on a carbonatom and substituted by phenyl-lower-alkoxycarbonyl on the nitrogen, oris unsubstituted on the nitrogen, and is preferably in the (R) form, the(R,S) form or, in particular, the (S) form at the binding carbon atom,and is, in particular, 2-oxopyrrolidin-5(S)-yl,(L)-trans-4-hydroxyprolyl or(L)-N-benzyloxycarbonyl-trans-4-hydroxyprolyl.

Tetrahydropyranyl is, in particular, tetrahydropyran-2-yl or -4-yl whichis preferably unsubstituted and is preferably bonded in the (R) form,(S) form or, in particular, the (R,S) form, provided it is bonded viathe 2 carbon atom.

Tetrahydrofuranyl is, in particular, tetrahydrofuran-3-yl which ispreferably unsubstituted and is preferably bonded in the (R) form, the(R,S) form or, in particular, the (S) form.

Thiazolidinyl is, in particular, thiazolidin-4-yl which is preferablyunsubstituted and is preferably in the (S) form, the (R,S) form or, inparticular, the (R) form (=(L) form) at the binding carbon atom.

Thiazolyl is, in particular, thiazol-4-yl which is preferablysubstituted by amino, such as 2-amino-4-thiazolyl.

Indolyl is, in particular, indol-2-yl which is preferably unsubstituted.

4H-1-Benzopyranyl is, in particular, 4H-1-benzopyran-2-yl which isunsubstituted or preferably substituted by oxo, such as4-oxo-4H-1-benzopyran-2-yl.

The oxo, hydroxyl and amino substituents of piperidinyl, pyrrolidinyl,tetrahydropyranyl, tetrahydrofuranyl, thiazolidinyl, thiazolyl, indolylor 4H-1-benzopyranyl which may be present are preferably bonded tocarbon, while the lower alkoxy, lower-alkoxycarbonyl andphenyl-lower-alkoxycarbonyl substituents are preferably bonded tonitrogen or carbon.

The lower-alkoxy radical in lower-alkoxy-lower-alkanoyl R₁ isunsubstituted or substituted by one or more, in particular by from 1 upto and including 3, of the said radicals, in particular (preferably fromone to, in particular, three times) by halogen, in particular fluorine;or (preferably once) by one of the remaining radicals mentioned, inparticular (preferably once) by lower alkoxy, in particular methoxy, or(preferably once) by pyrrolidinyl, in particular pyrrolidin-2-yl or-5-yl which is unsubstituted or, in particular, substituted by oxo; or,in addition, by phenyl, as in benzyloxycarbonyl.

In lower alkanoyl R₁, which is unsubstituted or substituted bypiperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl,thiazolidinyl, thiazolyl, indolyl, 4H-1-benzopyranyl, piperidinyloxy,pyrrolidinyloxy, tetrahydropyranyloxy, tetrahydrofuranyloxy,thiazolidinyloxy, thiazolyloxy, indolyloxy or 4H-1-benzopyranyloxy,which are in each case unsubstituted or substituted by one or more(preferably one) substituents selected, independently of each other,from oxo, hydroxyl, amino, lower alkyl, lower-alkoxycarbonyl andphenyl-lower-alkoxycarbonyl; lower alkanoyl is, in particular, formyl(in each case yields with one of the said radicals the correspondinglysubstituted carbonyl radical), acetyl or 2- or 3-propionyl, withpreferably the (R) form, (R,S) form or, in particular, the (S) formbeing present when the substituent is bonded in the 2 position, whilethe remaining radicals are defined as above. That which is preferred isN-lower-alkoxycarbonyl-piperidinyl-lower-alkanoyl, for example-carbonyl, such as N-ethoxycarbonyl-piperidin-4-ylcarbonyl,pyrrolidinyl-lower-alkanoyl, such as -carbonyl, which is substituted byhydroxyl on a carbon atom and/or by phenyl-lower-alkoxycarbonyl on thenitrogen atom and which is preferably in the (R) form, the (R,S) formor, in particular, the (S) form at the binding carbon atom, such as(L)-trans-4-hydroxyprolyl or(L)-N-benzyloxycarbonyl-trans-4-hydroxyprolyl,aminothiazolidinyl-lower-alkanoyl, for example-acetyl, such as2-amino-4-thiazolyl-acetyl, thiazolyl-lower-alkanoyl, for example-carbonyl, such as thiazol-2-ylcarbonyl, indolyl-lower-alkanoyl, forexample -carbonyl, such as indol-2-ylcarbonyl,4H-1-benzopyranyl-lower-alkanoyl, for example -carbonyl, which issubstituted by oxo, such as 4-oxo-4H-1-benzopyran-2-ylcarbonyl,N-lower-alkyl-piperidinyloxy-lower-alkanoyl, for example -carbonyl, suchas N-methylpiperidin-4-yloxycarbonyl,tetrahydropyranyloxy-lower-alkanoyl, for example -propionyl or-carbonyl, such as 2(S)-(tetrahydropyran-4-yloxy)propionyl ortetrahydropyran-2(R,S)-yloxycarbonyl, ortetrahydrofuranyloxy-lower-alkanoyl, for example -carbonyl, such astetrahydrofuran-3(S)-yloxycarbonyl.

Heterocyclyl is preferably an unsubstituted or substituted heterocyclicring having from 5 to 7, preferably 5 or 6, ring atoms in which 1 or 2ring carbon atoms are replaced by a hetero atom selected from O, N andS, is unsaturated or completely or partially saturated and can be asimple ring or be benzo-fused, cyclopenta-fused or cyclohexa-fused,where the substituents preferably are choosen, independently of eachother, from one or more (preferably one or two) substituents selectedfrom oxo, hydroxyl, amino, lower alkyl, lower-alkoxycarbonyl andphenyl-lower-alkoxycarbonyl; and is, in particular, selected frommorpholinyl, piperazinyl, for example piperazin-1-yl, pyridinyl, forexample pyridin-3-yl, piperidinyl, pyrrolidinyl, tetrahydropyranyl,tetrahydrofuranyl, thiazolidinyl, thiazolyl, indolyl and4H-1-benzopyranyl which are in each case unsubstituted or substituted byone or more radicals selected, independently of each other, from oxo,hydroxyl, amino, lower alkyl, lower-alkoxycarbonyl andphenyl-lower-alkoxycarbonyl, preferably unsubstituted or substituted byone or, in addition, two of the said radicals; and is primarilymorpholinyl, such as morpholin-4-yl, lower-alkylpiperazinyl, inparticular N-lower-alkyl-piperazinyl, for example4-lower-alkyl-piperazin-1-yl, such as 4-methyl-piperazin-1-yl, orpyridinyl, such as pyridin-3-yl. Ary is preferably C₆ -C₁₄ aryl, forexample phenyl, naphthyl, such as 1- or 2-naphthyl, or, in addition,fluorenyl, such as fluoren-9-yl, and is unsubstituted or substituted byone or more (preferably from one to three) radicals which are selected,independently of each other, from lower alkyl, phenyl-lower-alkyl,halogen, cyano, hydroxyl, lower alkoxy, phenyl-lower-alkoxy,lower-alkoxy-lower-alkoxy, lower-alkylenedioxy (bonded to two adjacentcarbon atoms of the respective aryl ring), pyridyl-lower-alkoxy andphenyl-lower-alkanesulfonyl which is unsubstituted or is substituted inthe phenyl radical by one or more radicals selected, independently ofeach other, from halogen, such as chlorine; and (alternatively or inaddition) from nitro; and is, in particular, phenyl.

In arylcarbonyl which is substituted by heterocyclyl orheterocyclyl-lower alkyl,-such as, in particular, -methyl, or inheterocyclylcarbonyl which is substituted (likewise by one or more ofthese radicals), aryl and heterocyclyl are as defined immediately above,preferably as indicated there as being preferred; preferably, only oneheterocyclyl or heterocyclyl-lower alkyl substituent is present.

Of these radicals, arylcarbonyl which is substituted once byheterocyclyl-lower-alkyl, and heterocyclylcarbonyl which is substitutedonce by heterocyclyl are preferred.

Arylcarbonyl which is substituted by heterocyclyl-lower alkyl is, inparticular, morpholinyl-lower-alkyl-benzoyl, such as4-(morpholin-4-ylmethyl)benzoyl.

Heterocyclylcarbonyl which is substituted by heterocyclyl is, inparticular, lower-alkylpiperazinyl-pyridylcarbonyl, such asN-lower-alkylpiperazinyl-pyridylcarbonyl, in particular4-lower-alkyl-piperazin-1-yl-pyridylcarbonyl, for example 2- or3-(4-lower-alkyl such as methyl!-piperazin-1-yl)pyridin-2-ylcarbonyl or-3-ylcarbonyl.

Phenyl-lower-alkanoyl (in this context, the term "phenyl-lower-alkanoyl"also includes benzoyl=phenylcarbonyl) which is substituted by hydroxyland lower alkyl preferably has, in each case, a hydroxyl and a loweralkyl substituent, in particular hydroxyl and methyl or ethyl, on thephenyl ring and is, in particular, correspondingly substituted benzoyl,such as 3-hydroxy-2-methylbenzoyl.

Arylsulfonyl (=aryl-SO₂ --) preferably contains, as aryl, a radical asdefined above, in particular phenyl which is substituted by amino,nitro, amino and lower alkyl or nitro and lower alkyl, and is primarily4-nitrobenzenesulfonyl, 4-aminobenzenesulfonyl, 2-lower-alkyl(inparticular 2-methyl)-4-nitrobenzenesulfonyl or 4-amino-2-lower-alkyl(inparticular 2-methyl)-benzenesulfonyl.

The respective radicals which come within the definition of"phenyl-lower-alkanoyl which is substituted by hydroxyl and lower alkyl"and "arylsulfonyl" R₁ can both above and below, at all levels ofdefinition of R₁, also stand alone or be omitted.

A residue of an amino acid, which residue is bonded via the carbonylgroup (of its carboxyl group, which is present in the corresponding freeamino acid), to the binding nitrogen, i.e. can be obtained by removingthe OH group in the carboxyl group (-COOH), is selected from glycine(H-Gly-OH), alanine (H-Ala-OH), 2-aminobutyric acid,⁻ 3-aminobutyricacid, 4-aminobutyric acid, 3-aminopentanoic acid, 4-aminopentanoic acid,5-aminopentanoic acid, 3-aminohexanoic acid, 4-aminohexanoic acid or5-aminohexanoic acid, valine (H-Val-OH), norvaline (α-aminovalericacid), leucine (H-Leu-OH), isoleucine (H-Ile-OH), norleucine(α-aminohexanoic acid, H-Nle-OH), serine (H-Ser-OH), homoserine(α-amino-γ-hydroxybutyric acid), threonine (H-Thr-OH), methionine(H-Met-OH), cysteine (H-Cys-OH), phenylalanine (H-Phe-OH), tyrosine(H-Tyr-OH), 4-aminophenylalanine, 4-chlorophenylalanine,4-carboxyphenylalanine, β-phenylserine (β-hydroxyphenylalanine),phenylglycine, o-naphthylalanine (H-Nal-OH), cyclohexylalanine(H-Cha-OH), cyclohexylglycine, tryptophan (H-Trp-OH), asparatic acid(H-Asp-OH), β-phenyl-lower-alkyl aspartate, such as β-benzyl aspartate,asparagine (H-Asn-OH), aminomalonic acid, aminomalonic acid monoamide,glutamic acid (H-Glu-OH), glutamine (H-Gln-OH), histidine (H-His-OH),arginine (H-Arg-OH), lysine (H-Lys-OH), δ-hydroxylysine, ornithine(α,δ-diaminovaleric acid), 3-aminopropanoic acid, α,γ-diaminobutyricacid and α,β-diaminopropionic acid; and preferably selected from valine,norvaline, leucine, isoleucine and norleucine, and, in addition, fromserine, homoserine, threonine, methionine, cysteine, phenylalanine,tyrosine, 4-aminophenylalanine, 4-chlorophenylalanine,4-carboxyphenylalanine, β-phenylserine, phenylglycine,α-naphthylalanine, cyclohexylalanine, cyclohexylglycine, tryptophan,asparatic acid, β-phenyl-lower-alkyl aspartate, such as β-benzylaspartate, asparagine, aminomalonic acid monoamide, glutamic acid,γ-phenyl-lower-alkyl glutamate, such as γ-benzyl glutamate, glutamine,histidine, arginine, lysine, δ-hydroxylysine and ornithine; withβ-benzyl aspartate, aspartic acid, asparagine or in particular, valinebeing particularly preferred; with the respective amino group(s) andother functional groups being free or (if possible) in salt form; andwith the said amino acid radicals having asymmetric carbon atoms beingin the (D) form, the (L) form or the (D,L) form, preferably in the (L)form.

In a residue of one of the latter amino acids which is bonded via thecarbonyl group and which is N-acylated on the amino nitrogen by one ofthe previously mentioned acyl radicals, the acyl radicals are selectedfrom lower alkoxy-lower-alkanoyl, in which the lower-alkoxy radical isunsubstituted or is substituted by one or more radicals selected,independently of each other, from halogen and lower alkoxy, and, inaddition, phenyl, or by a radical selected from piperidinyl,pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolidinyl,thiazolyl, indolyl or 4H-1-benzopyranyl which are unsubstituted orsubstituted by one or more radicals selected, independently of eachother, from oxo, hydroxyl, amino, lower alkyl, lower-alkoxycarbonyl andphenyl-lower-alkoxycarbonyl; lower alkanoyl which is unsubstituted or issubstituted by piperidinyl, pyrrolidinyl, tetrahydropyranyl,tetrahydrofuranyl, thiazolidinyl, thiazolyl, indolyl, 4H-1-benzopyranyl,piperidinyloxy, pyrrolidinyloxy, tetrahydropyranyloxy,tetrahydrofuranyloxy, thiazolidinyloxy, thiazolyloxy, indolyloxy or4H-1-benzopyranyloxy which are in each case unsubstituted or substitutedby one or more substituents selected, independently of each other, fromoxo, hydroxyl, amino, lower alkyl, lower-alkoxycarbonyl andphenyl-lower-alkoxycarbonyl; arylcarbonyl or heterocyclylcarbonyl whichis substituted by heterocyclyl or heterocyclyl-lower alkyl;(alternatively or additionally) phenyl-lower-alkanoyl which issubstituted by hydroxyl and lower alkyl; and (alternatively oradditionally) arylsulfonyl; where the said acyl radicals are preferablydefined as above; while the amino acid residue is selected from theresidues mentioned above for residues of an amino acid which are bondedvia the carbonyl group, in particular from the residues mentioned thereas being preferred. That which is particularly preferred islower-alkoxy-lower-alkanoyl-valyl, such as lower-alkoxycarbonyl-valyl,for example methoxycarbonyl-valyl, or thiazolidinyl-valyl, in particularthiazolidin-4-yl-valyl, which is preferably in the (S) form, the (R,S)form or, in particular the (R) form (=(L) form) at the 4-carbon atom ofthe thiazolidine ring; with the valyl residue in each case preferablybeing in the (L) form; or, in addition, aspartyl,N-phenyl-lower-alkoxycarbonyl-(L)-β-(O-phenyl-lower-alkyl)aspartyl, suchas N-benzyloxycarbonyl-(L)-β-(O-benzyl)-aspartyl, asparaginyl orN-phenyl-lower-alkoxycarbonyl-asparaginyl, such asN-benzyloxycarbonyl-asparaginyl.

R₁ is primarily selected from tert-butoxycarbonyl,2,2,2-trifluoroethoxy-carbonyl, 2-(methoxy)ethoxy-carbonyl,5(S)-2-oxo-pyrrolidinyl-methoxycarbonyl,1-ethoxycarbonyl-piperidin-4-ylcarbonyl, trans-(L)-4-hydroxyprolyl,N-(benzyloxycarbonyl)-trans-(L)-4-hydroxyprolyl,(L)-thiazolidin-4-ylcarbonyl, indol-2-ylcarbonyl,4H-1-benzopyran-2-ylcarbonyl, N-methyl-piperidinyloxycarbonyl,tetrahydropyran-2(R,S)-ylcarbonyl, O-(tetrahydropyran-4-yl)-(L)-lactoyl(=2(S)-(tetrahydropyran-4-yloxy)propionyl),3(S)-tetrahydrofuranyloxycarbonyl, 2-amino-thiazol-4-ylacetyl,6-(4-methyl-piperazin-1-yl)-pyridin-3-ylcarbonyl,4-(morpholin-4-ylmethyl)-benzoyl, N-methoxycarbonyl-(L)-valyl and N-(L)-thiazolidin-4-ylcarbonyl!-(L)-valyl, and, in addition, from(L)-asparaginyl, N-benzyloxycarbonyl-(L)-asparaginyl, (L)-aspartyl andN-benzyloxycarlbonyl-(L)-β-(O-benzyl)-aspartyl, or is (alternatively oradditionally) selected from methoxycarbonyl,2-methoxy-1(R,S)-methyl-ethoxycarbonyl,1,1-dimethyl-2-methoxyethoxycarbonyl and 3-hydroxy-2-methylbenzoyl.Cyclohexyl, cyclohexenyl, phenyl, naphthyl (such as 1- or 2-naphthyl) ortetrahydronaphthyl R₂ and R₃ are, independently of each other,unsubstituted or substituted, as indicated, with the substituents phenylor cyanophenyl being alternative or additional with respect to the groupof the other substituents mentioned; and with lower-alkylenedioxy beinglinked to 2, preferably adjacent, carbon atoms of the respective ring.Preferably, cyclohexenyl and tetrahydronaphthyl are unsubstituted, whilecyclohexyl and, in particular, phenyl and naphthyl are unsubstituted orsubstituted by one, two or three radicals which are selected,independently of each other, from lower alkyl, in particular methyl;phenyl (alternatively or additionally); cyanophenyl, in particular2-cyanophenyl (alternatively or additionally); phenyl-lower-alkyl, inparticular 2-phenylethyl, halogen, in particular fluorine, cyano,hydroxyl, lower alkoxy, in particular methoxy or, in addition,iso-butoxy, lower-alkoxy-lower-alkoxy, in particular 2-methoxyethoxy,lower-alkylenedioxy, in particular ethylene-1,2-dioxy or, in particular,methylenedioxy, which is linked to 2 adjacent carbon atoms of therespective ring, phenyl-lower-alkoxy, in particular benzyloxy,pyridyl-lower-alkoxy, in which pyridyl is bonded via a ring carbon atom,such as pyridin-2-, pyridin-3- or, in addition, pyridin-4-ylmethoxy, andphenyl-lower-alkanesulfonyl (=phenyl-lower-alkyl-S(═O)₂ --) which isunsubstituted or is substituted, in particular in the phenyl radical, byone or more, in particular 2, radicals selected from halogen, inparticular chlorine, in particular dichlorophenyl-lower-alkanesulfonyl,such as 2,6-dichlorobenzylsulfonyl (=2,6-dichlorophenylmethanesulfonyl),and, in addition, from halo-lower-alkyl, preferably having not more than3 halogen atoms, in particular fluorine atoms, for exampletrifluoromethyl, lower-alkoxycarbonyl-lower alkoxy, such asethoxycarbonylmethoxy, carboxy-lower-alkoxy, such as carboxymethoxy,hydroxy-lower-alkoxy having at least two carbon atoms, in which hydroxylis not bonded in the 1 position, such as 2-hydroxyethoxy,carbamoyl-lower-alkoxy, such as carbamoylmethoxy (H₂ N--C(═O)--CH₂--O--), and cyano-lower-alkoxy, such as cyanomethoxy.

Preferably, R₂ and R₃ are selected from cyclohexyl, cyclohexenyl, suchas cyclohexen-1-yl, phenyl, phenyl-lower-alkoxy-phenyl, in particular4-phenyl-lower-alkoxyphenyl, such as 4-(benzyloxy)phenyl,difluorophenyl, in particular 2,4-difluorophenyl, cyanophenyl, inparticular 4-cyanophenyl, lower-alkoxyphenyl, such as 2-, 3- or4-lower-alkoxyphenyl, for example 4-isobutyloxyphenyl and, inparticular, 2-, 3- and, in particular, 4-methoxyphenyl,tri-lower-alkoxy-phenyl, in particular trimethoxyphenyl, for examplehaving the lower-alkoxy substituents in the 3,4,5 positions, as in3,4,5-trimethoxyphenyl, in the 2,4,5 positions, as in2,4,5-trimethoxyphenyl, in 2,4,6 positions, as in2,4,6-trimethoxyphenyl, where the tri-lower alkoxy radicals or methoxyradicals preferably being bonded asymmetrically on the phenyl ring,primarily in the 2,3,4 positions, for example in 2,3,4-trimethoxyphenyl,lower-alkoxy-lower-alkoxy-phenyl, such as4-(lower-alkoxy-lower-alkoxy)phenyl, especially4-(2-methoxy-ethoxy)phenyl, lower-alkylenedioxyphenyl, in which thelower-alkylenedioxy radical is bonded via its two oxygen atoms to twoadjacent carbon atoms of the phenyl ring, for examplemethylenedioxyphenyl, such as 3,4-methylenedioxyphenyl, andpyridyl-lower-alkoxyphenyl, such as 4-(pyridin-2- orpyridin-3-yl-lower-alkoxy)phenyl, in particularpyridin-3-yl-loweralkoxyphenyl, for example pyridin-3-yl-methoxyphenyl;and, in addition, from 4-lower-alkoxy-2-fluorophenyl, such as4-methoxy-2-fluorophenyl, 4-fluoro-2-loweralkoxyphenyl, such as4-fluoro-2-methoxyphenyl, 4-lower-alkoxy-2-hydroxyphenyl, such as4-methoxy-2-hydroxyphenyl, phenyl which is substituted not more thanthree times by lower alkyl, such as methyl, and lower alkoxy, such asmethoxy, such as 4-lower-alkoxy-2,3-di-lower-alkylphenyl, for example4-methoxy-2,3-dimethylphenyl, phenyl-lower-alkylphenyl, such as4-phenyl-lower-alkylphenyl, for example 4-(2-phenylethyl)-phenyl,fluorophenyl, such as 2-fluorophenyl, hydroxyphenyl, such as4-hydroxyphenyl, di-lower-alkoxyphenyl, in particular dimethoxyphenyl,for example 2,4-di-lower-alkoxyphenyl, such as 2,4-dimethoxyphenyl,3,4-di-lower-alkoxyphenyl, such as 3,4-dimethoxyphenyl,2,5-di-lower-alkoxyphenyl, such as 2,5-dimethoxyphenyl, or2,6-di-lower-alkoxyphenyl, such as 2,6-dimethoxyphenyl,tetrahydronaphthyl, in particular 5,6,7,8-tetrahydro-1-naphthyl,halonaphthyl, such as fluoronaphthyl, in particular 4-fluoronaphthyl,cyanonaphthyl, in particular 4-cyanonaphthyl, lower-alkoxynaphthyl, inparticular 4-lower-alkoxynaphthyl, such as 4-methoxy-1-naphthyl, anddihalophenyl-lower-alkanesulfonylphenyl, in particulardichlorophenyl-lower-alkanesulfonylphenyl, such as4-(2,6-dichlorobenzylsulfonyl)phenyl; or, alternatively or additionallyto the previously mentioned radicals, selected from biphenylyl, such as4-biphenylyl, and (cyanophenyl)phenyl, such as 2'-cyanobiphenyl-4-yl.

Compounds of the formula I are particularly preferred in which R₃ is2,3,4-tri-lower-alkoxyphenyl, in particular 2,3,4-trimethoxyphenyl,while the remaining radicals R₁, R₂, R₄, R₅ and n are as defined aboveor below.

Compounds of the formula I are preferred in which the followingcombinations of R₂ and R₃ are present:

    ______________________________________    Radical R.sub.2                   Radical R.sub.3    ______________________________________     1) 4-(Phenyl-lower-alkoxy)-                       4-(Phenyl-lower-alkoxy)-        phenyl, in particular                       phenyl, in particular        4-(benzyloxy)phenyl                       4-(benzyloxy)phenyl     2) Phenyl         Cyanophenyl, in particular 4-cyanophenyl     3) Phenyl         2-Fluorophenyl     4) Phenyl         2,4-Difluorophenyl     5) Phenyl         4-Phenyl-lower-alkylphenyl, in particular                       4-(2-phenylethyl)phenyl     6) Phenyl         4-Lower-alkoxyphenyl, in particular                       4-methoxyphenyl or, in addition,                       4-isobutoxyphenyl     7) Phenyl         Dichlorophenyl-lower-alkanesul-                       fonylphenyl,                       in particular 4-(2,6-dichlorobenzyl-                       sulfonyl)phenyl     8) 4-(Lower alkoxy-lower-                       4-(Phenyl-lower-alkoxy)phenyl,        alkoxy)phenyl, in par-                       in particular        ticular 4-(2-methoxy-                       4-(benzyloxy)phenyl        ethoxy)phenyl     9) 4-(Lower-alkoxy-lower-                       Hydroxyphenyl, in particular        alkoxy)phenyl, in par-                       4-hydroxyphenyl        ticular 4-(2-methoxy-        ethoxy)phenyl    10) 4-(Lower-alkoxy-lower-                       4-(Lower alkoxy)phenyl,        alkoxy)phenyl, in par-                       in particular 4-methoxyphenyl        ticular 4-(2-methoxy-        ethoxy)phenyl    11) 4-(Lower-alkoxy-lower-                       4-(Lower-alkoxy-lower-alkoxy)-        alkoxy)phenyl, in par-                       phenyl, in particular        ticular 4-(2-methoxy-                       4-(2-methoxyethoxy)phenyl        ethoxy)phenyl    12) 4-(Phenyl-lower-alkoxy)-                       4-(Lower alkoxy)phenyl,        phenyl, in particular                       in particular        4-(benzyloxy)phenyl                       4-methoxyphenyl    13) 4-Hydroxyphenyl                       4-(Lower alkoxy)-                       phenyl, in particular                       4-methoxyphenyl    14) 4-(Lower alkoxy)phenyl,                       4-Lower alkoxyphenyl,        in particular  in particular        4-methoxyphenyl or                       4-methoxyphenyl        4-isobutoxyphenyl    15) 4-(Lower alkoxy)phenyl,                       Phenyl        in particular        4-methoxyphenyl    16) Cyclohexyl     4-Lower-alkoxyphenyl,                       in particular                       4-methoxyphenyl    17) Phenyl         4-Lower-alkoxy-2-fluorophenyl,                       in particular 4-methoxy-                       2-fluorophenyl    18) Phenyl         4-Fluoro-2-lower-alkoxyphenyl,                       in particular 4-fluoro-2-methoxyphenyl    19) Phenyl         4-Lower-alkoxy-2-hydroxyphenyl,                       in particular 4-methoxy-                       2-hydroxyphenyl    20) 4-Lower-alkoxyphenyl,                       Cyclohexyl        in particular        4-methoxyphenyl    21) 4-Lower-alkoxyphenyl,                       Cyclohexen-1-yl        in particular        4-methoxyphenyl    22) Cyclohexyl     4-(Phenyl-lower-alkoxy)phenyl,                       in particular                       4-(benzyloxy)phenyl    23) Cyclohexyl     4-Hydroxyphenyl    24) Phenyl         Phenyl    25) Phenyl         4-(Phenyl-lower-alkoxy)phenyl,                       in particular                       4-(benzyloxy)phenyl    26) Phenyl         4-((Pyridin-2-yl- or                       pyridin-3-yl)lower alkoxy)-                       phenyl, in particular                       4-(pyridin-2-yl- or, especially,                       pyridin-3-yl)methoxyphenyl    27) Phenyl         3,4-Lower-alkylenedioxyphenyl,                       in particular                       3,4-methylenedioxyphenyl    28) Phenyl         3,4-Di-lower-alkoxyphenyl,                       in particular                       3,4-dimethoxyphenyl    29) Phenyl         3-Lower-alkoxyphenyl,                       in particular                       3-methoxyphenyl    30) Phenyl         2,3,4-Tri-lower-alkoxyphenyl,                       in particular                       2,3,4-trimethoxyphenyl    31) Phenyl         3,4,5-Tri-lower-alkoxyphenyl,                       in particular                       3,4,5-trimethoxyphenyl    32) Phenyl         2,4-Di-lower-alkoxyphenyl,                       in particular                       2,4-dimethoxyphenyl    33) Phenyl         2-(Lower alkoxy)phenyl,                       in particular                       2-methoxyphenyl    34) Phenyl         4-Lower-alkoxy-2,3-di-                       lower-alkylphenyl,                       in particular 4-methoxy-2,3-                       dimethylphenyl    35) Phenyl         2,4,5-Tri-lower-alkoxyphenyl,                       in particular                       2,4,5-trimethoxyphenyl    36) Phenyl         2,4,6-Tri-lower-alkoxyphenyl,                       in particular                       2,4,6-trimethoxyphenyl    37) Phenyl         5,6,7,8-Tetrahydro-1-naphthyl-    38) Phenyl         2,5-Di-lower-alkoxyphenyl,                       in particular                       2,5-dimethoxyphenyl    39) Phenyl         2,6-Di-lower-alkoxyphenyl,                       in particular                       2,6-dimethoxyphenyl    40) Phenyl         Lower-alkoxy-naphthyl,                       in particular                       4-methoxy-1-naphthyl    41) Phenyl         Cyano-naphthyl, in particular                       4-cyano-1-naphthyl    42) Phenyl         Fluoronaphthyl, in particular                       4-fluoro-1-naphthyl    43) Cyclohexyl     2,3,4-Tri-lower-alkoxyphenyl,                       in particular                       2,3,4-trimethoxyphenyl    44) Cyclohexyl     4-(Lower-alkoxy-lower-alkoxy)-                       phenyl, in particular                       4-(2-methoxyethoxy)phenyl    45) Cyclohexyl     3,4-Lower-alkylenedioxyphenyl,                       in particular                       3,4-methylenedioxyphenyl    46) Cyclohexyl     3,4-Di-lower-alkoxyphenyl,                       in particular                       3,4-dimethoxyphenyl    47) Cyclohexyl     3-Lower-alkoxyphenyl,                       in particular                       3-methoxyphenyl    48) Cyclohexyl     3,4,5-Tri-lower-alkoxyphenyl,                       in particular                       3,4,5-trimethoxyphenyl    49) Cyclohexyl     2,4-Di-lower-alkoxyphenyl,                       in particular                       2,4-dimethoxyphenyl    50) Cyclohexyl     2-(Lower alkoxy)phenyl,                       in particular                       2-methoxyphenyl    51) Cyclohexyl     4-Lower-alkoxy-2,3-di-lower-                       alkylphenyl, in particular                       4-methoxy-2,3-dimethylphenyl    52) Cyclohexyl     2,4,5-Tri-lower-alkoxyphenyl,                       in particular                       2,4,5-trimethoxyphenyl    53) Cyclohexyl     2,4,6-Tri-lower-alkoxyphenyl,                       in particular                       2,4,6-trimethoxyphenyl    54) Cyclohexyl     5,6,7,8-Tetrahydro-1-naphthyl-    55) Cyclohexyl     2,5-Di-lower-alkoxyphenyl,                       in particular                       2,5-dimethoxyphenyl    56) Cyclohexyl     2,6-Di-lower-alkoxyphenyl,                       in particular                       2,6-dimethoxyphenyl    57) Cyclohexyl     Lower-alkoxy-naphthyl,                       in particular                       4-methoxy-1-naphthyl    58) Cyclohexyl     Cyano-naphthyl, in particular                       4-cyano-1-naphthyl    59) Cyclohexyl     Fluoronaphthyl, in particular                       4-fluoro-1-naphthyl         or alternatively or         additionally:    60) Phenyl         Biphenylyl, in particular                       4-biphenylyl    61) 4-(Phenyl-lower-alkoxy)-                       Biphenylyl, in particular        phenyl, in particular                       4-biphenylyl        4-benzyloxyphenyl    62) 4-Hydroxyphenyl                       Biphenylyl, in particular                       4-biphenylyl    63) 4-Lower-alkoxyphenyl,                       Biphenylyl, in particular        in particular  4-biphenylyl        4-methoxyphenyl    64) Phenyl         (Cyanophenyl)phenyl, in                       particular 2'-cyanobiphenyl-4-yl    65) 4-(Phenyl-lower-alkoxy)-                       (Cyanophenyl)phenyl, in        phenyl, in particular                       particular 2'-cyanobiphenyl-4-yl        4-benzyloxyphenyl    66) 4-Hydroxyphenyl                       (Cyanophenyl)phenyl, in                       particular 2'-cyanobiphenyl-4-yl    67) 4-Lower-alkoxyphenyl,                       (Cyanophenyl)phenyl, in        in particular  particular 2'-cyanobiphenyl-4-yl        4-methoxyphenyl    68) Cyclohexyl     (Cyanophenyl)phenyl, in                       particular 2'-cyanobiphenyl-4-yl    69) Cyclohexyl     4-Lower-alkoxyphenyl, in                       particular 4-methoxyphenyl    70) Phenyl         4-Hydroxyphenyl    ______________________________________

The combinations R₂ and R₃ which are very particularly preferred arethose mentioned immediately above under numbers 2), 4), 6), 8), 16),24), 26), 27), 30) and 44), especially those mentioned under 6) and, inparticular, under 30).

R₄ is preferably lower alkyl, in particular methyl or isopropyl, or elsesec-butyl (=1-methylpropyl).

Lower alkyl R₅ is preferably methyl or else ethyl.

The variable n is preferably 1.

Salts of compounds of the formula I are, in particular (when basicgroups are present in compounds of the formula I), acid addition salts,salts with bases (when acidic groups are present in compounds of theformula I) or else possibly mixed salts or internal salts when severalsalt-forming groups are present.

Salts are primarily the pharmaceutically utilizable, non-toxic salts ofcompounds of the formula I.

Such salts are formed, for example, from compounds of the formula Ihaving an acidic group, for example a carboxyl group, a sulfo group or aphosphoryl group which is substituted by one or two hydroxyl groups, andare, for example, their salts with suitable bases, such as non-toxicmetal salts derived from metals of groups Ia, Ib, IIa and IIb of theperiodic system of the elements, primarily suitable alkali metal salts,for example lithium, sodium or potassium salts, or alkaline earth metalsalts, for example magnesium or calcium salts, and also zinc salts orammonium salts, and also those salts which are formed with organicamines, such as mono-, di- or trialkylamines, in particular mono-, di-or tri-lower-alkylamines, which are unsubstituted or substituted byhydroxyl, or with quaternary ammonium compounds, for example withN-methyl-N-ethylamine, diethylamine, triethylamine, mono-, bis- ortris-(2-hydroxy-lower-alkyl)amines, such as mono-, bis- ortris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine ortris-(hydroxymethyl)methylamine,N,N-di-lower-alkyl-N-(hydroxy-lower-alkyl)amines, such asN,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine,N-methyl-D-glucamine or quaternary ammonium salts, such astetrabutylammonium salts. The compounds of the formula I which have abasic group, for example an amino group, can form acid addition salts,for example with inorganic acids, for example hydrohalic acid, such ashydrochloric acid, sulfuric acid or phosphoric acid, or with organiccarboxylic, sulfonic, sulfato (--O--SO₃ H) or phospho acids orN-substituted sulfamic acids, for example acetic acid, propionic acid,glycolic acid, succinic acid, maleic acid, hydroxymaleic acid,methylmaleic acid, fumaric acid, malic acid, tartaric acid, gluconicacid, glucaric acid, glucuronic acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid,2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinicacid or isonicotinic acid, and, in addition, with amino acids, forexample the α-amino acids mentioned above, in particular glutamic acidand aspartic acid, and also with methanesulfonic acid, ethanesulfonicacid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid,benzenesulfonic acid, 4-methylbenzenesulfonic acid,naphthalene-2-sulfonic acid, 2- or 3-phosphoglycerate,glucose-6-phosphate or N-cyclohexylsulfamic acid (with the formation ofcyclamates), or with other acidic organic compounds, such as ascorbicacid. Compounds of the formula I which possess acidic and basic groupscan also form internal salts.

Pharmaceutically unsuitable salts, for example perchlorates or picrates,may also be used for isolation or purification. Only thepharmaceutically utilizable salts, which are non-toxic when properlyused, are suitable for therapeutic use, and are, therefore, preferred.

The compounds of the formula I have valuable pharmacological properties.They possess anti-retroviral activity, particularly against the HIV-1and HIV-2 viruses, which are considered to be causative agents of AIDS,and surprisingly have synergistic effects when used in combination withother compounds which possess activity against retroviral aspartateproteases. The compounds of the formula I are inhibitors of retroviralaspartate proteases, in particular inhibitors of the aspartate proteaseof HIV-1 or HIV-2, and are therefore suitable for treating retroviraldiseases, such as AIDS or its preliminary stages (e.g. ARDS). Compoundsof the formula I also have an effect against corresponding animalretroviruses, such as SIV (in monkeys) or FIV (in cats).

In this context, compounds of the formula I have particularlyadvantageous pharmacodynamic properties, for example goodpharmacodynamics, such as a high bioavailability and/or high bloodlevels (especially when administered orally), and/or good tolerability.

The inhibitory effect of the compounds of the formula I on theproteolytic activity of HIV-1 protease can be demonstrated, for example,using a method analogous to that described by A. D. Richards et al., J.Biol. Chem. 265(14), 7733-7736 (1990). In this case, inhibition of theaction of the HIV-1 protease (prepared in accordance with S. Billich etal., J. Biol. Chem. 263(34), 17905-17908 (1990)) is measured in thepresence of the icosapeptide RRSNQVSQNYPIVQNIQGRR (an artificialsubstrate of HIV-1 protease, prepared by peptide synthesis using knownmethods, see J. Schneider et al., Cell 54, 363-368 (1988)), which, as asubstrate analogue, comprises one of the cleavage sites of the gagprecursor protein (natural substrate of the HIV-1 protease). Thissubstrate and its cleavage products are analysed by high performanceliquid chromatography (HEPLC).

The active compound to be tested is dissolved in dimethyl sulfoxide. Theenzymic test is carried out by adding suitable dilutions of theinhibitor in 20 mM β-morpholinoethanesulfonic acid (MES) buffer pH 6.0,to the test mixture. The latter consists of the abovementionedicosapeptide (122 μM) in 20 mM MES buffer, pH 6.0. 100 μl are employedper test mixture. The reaction is started by adding 10 μl of HIV-1protease solution, and is ended after one hour of incubation at 37° C.by adding 10 μl of 0.3 M HClO₄. After the sample has been centrifuged at10,000×g for 5 min, 20 μl of the resulting supernatant are loaded onto a125×4.6 mm ®Nucleosil C18-5μ HPLC column (reverse-phase material fromMacherey & Nagel, Duren, FRG, based on silica gel which is coated withC₁₈ alkyl chains). The uncleaved icosapeptide and its cleavage productsare eluted from the column using the following gradient: 100% eluent1→50% eluent 1+50% eluent 2 (eluent 1: 10% acetonitrile, 90% H₂ O, 0.1%trifluoroacetic acid (TFA); eluent 2: 75% acetonitrile, 25% H₂ O, 0.08%TFA) over 15 min, flow rate 1 ml/min The eluted peptide fragments arequantified by measuring the peak height of the cleavage product at 215nm.

Compounds of the formula I have inhibitory effects in the range from10⁻⁵ to 10⁻⁹ M. In this context, IC₅₀ values (IC₅₀ =that concentrationwhich decreases the activity of the HIV-1 protease by 50% as comparedwith the activity of a control without inhibitor) of from about 5×10⁻⁵to 10⁻⁹ M are preferably obtained.

In a further test, it can be shown that compounds of the formula Ieither protect cells which are normally infected by HIV from such aninfection or at least retard such an infection. This test uses the humanT cell leukaemia cell line MT-2 (Science 229, 563 (1985)), which isextremely sensitive to the cytopathic effect of HIV since it continuallyproduces HTLV-I (a virus which causes leukaemia). The MT-2 cells aregrown in RPMI 1640 medium (Gibco, Scotland; RPMI comprises an amino acidmixture lacking glutamine) which is supplemented with 10%heat-inactivated foetal calf serum, glutamine and standard antibiotics.The cells are always free of mycoplasmas. The HIV-1 virus (strain LAV)is cultured in A 3.01 cells (NIH, Bethesda, USA), a cell line which isused for culturing HIV-1 and which derives from the CEM cell line.Measuring by the test for reverse transcriptase (see below) indicatesthat the titre of the virus preparation is 2×10⁷ IU/ml.

In order to measure the infection-inhibiting effect of the testcompounds, 50 μl of the respective test substance in culture medium and100 μl of HIV-1 in culture medium (800 TCID50/ml, TCID50=tissue cultureinfective dose=dose, which infects 50% of the MT-2 cells) are added to10×10⁴ exponentially growing MT-2 cells which are initially introducedin 50 μl of culture medium on 96-well microtitre plates. After 4 days ofincubation, a sample consisting of 10 μl of the supernatant is removedfrom each well for measuring the reverse transcriptase activity. Thetitre of the reverse transcriptase enzyme, which is specific forretroviruses, is used as a measure of the virus titre. For determiningthe titre, the samples which have been removed are first added toanother 96-well microtitre plate and stored at -20° C. until measured.

When carrying out the measurement, 30 μl of reverse transcriptasecocktail are added to each well. The reverse transcriptase cocktailconsists of 50 mM Tris (α,α,α-tris(hydroxymethyl)methylamine, Ultraput-, Merck, Germany), pH 7.8; 75 mM KCl, 2 mM dithiothreitol, 5 mMMgCl₂ ; 0.1% Nonidet P-40 (detergent; Sigma, Switzerland), 0.8 mM EDTA,10 μg/ml poly-A (Pharrnacia, Uppsala, Sweden) and 0.16 μg/ml oligo(T)(=pdT(12-18), Pharmacia, Uppsala, Sweden) as template primer. Themixture is filtered through a 0.45 μm Acrodisc filter (Gelman SciencesInc., Ann Arbor, USA) and stored at -20° C. Prior to the test, 0.1%(v/v) of alpha-³² P!dTTP is added to aliquots of the solution to producea final radioactivity of 10 μCi/ml.

After mixing has taken place, the plate is incubated at 37° C. for 2 h.5 μl of the reaction mixture are then transferred to DE81 paper(Whatman, one filter per well). The dried filters are washed three timesfor 5 min with 300 mM NaCl/25 mM trisodium citrate and then once withethanol, and air-dried once again. The radioactivity on the filters ismeasured in a Packard Matrix 96-well counter (Packard, Zurich,Switzerland). The ED90 values are calculated and are defined as theconcentrations of the test compounds which reduce the RT activity by 90%as compared with that of a control without test compound.

In this test, the compounds of the formula I preferably inhibit virusreplication at concentrations of from 5×10⁻⁵ to 10⁻⁸ M.

Thus, the compounds of the formula I are suitable for actively retardingthe replication of HIV-1 in cell cultures.

It is also possible to measure the blood levels of compounds of theformula I.

For this purpose, the compounds of the formula I which are to beinvestigated are dissolved, for example, in dimethyl sulfoxide (DMSO) ata concentration of 240 mg/ml. The resulting solutions are diluted with20% (w/v) hydroxypropyl-β-cyclodextrin (HPβCD) in order to obtain aconcentration of the test substance of 12 mg/ml. This solution isadministered orally to mice, by means of artificial feeding by gavage,at a dose of 120 mg/kg. The animals are sacrificed at 30, 60, 90 and 120min after the administration, and blood is removed. From three to fouranimals are examined at each time point. The blood is heparinized andworked up for the analysis as follows: an internal standard is added tothe heparinized blood to give a final concentration of 4 μM. The bloodis centrifuged. 0.25 ml of plasma are taken off and deproteinized withan equal volume of acetonitrile. After centrifugation, the supernatantis dried in vacuo and the residue is suspended in 20 μl of a 3M solutionof NaCl and 100 μl of 0.05 M phthalate buffer having a pH of 3.0. Thesuspension is extracted firstly with 1 ml, and then with 0.2 ml, ofdiisopropyl ether. The diisopropyl ether solution is evaporated todryness and the residue is dissolved in 50% (v/v) of aqueousacetonitrile. This solution is examined by reversed-phase HPLC.

The reversed-phase HPLC analysis is carried out using a 125×4.6 mmNucleosil® C₁₈ column (reversed-phase material from Macherey-Nagel,Dfiren, Federal Republic of Germany, based on silica gel which has beenderivatized with hydrocarbon residues of 18 carbon atoms), which isequilibrated with a mobile phase of 50% acetonitrile in water/0.1%trifluoroacetic acid. The flow rate is 1 ml/min. Detection takes placeat 215 nm. Standards for the compounds in blood are worked up in analogywith the blood samples and are used for constructing standard curveswhich are then employed for deterimining the in-vivo concentrations.

These and related experiments, and also experiments involving parenteraladministration, demonstrate that using the compounds of the formula I,blood levels can be obtained which are greater than the ED₉₀ in theabovementioned cell assay. For this reason, compounds of this nature arealso suitable for preventing virus growth in vivo. The combination ofaspartate protease inhibition in vitro, inhibition of viral replicationin cell culture and measurement of the blood levels in rodents, such asrat or mouse, is used for determining the clinical potential ofaspartate protease inhibitors (see, for example, Roberts, N. A., et al.,Biochemical Soc. Transactions 20, 513-516 (1992)).

Blood levels which are greater than the ED₉₀ in the abovementioned cellassay can also be observed when compounds of the formula I areadministered (for example orally) to dogs. Consequently, the combinationof the data from the cell experiment, the blood levels in rodents andthe blood levels in dogs also renders plausible the possibility of usingthe compounds to treat retroviral diseases, in particular the saiddiseases, in other mammals, such as humans.

The compounds of the formula I can also be used for the prevention,control and therapy of infections due to retroviruses, in particularHIV, such as HIV-1 or HIV-2, in cell cultures, in particular cellcultures of lymphocyte cell lines from mammals, which is particularlyadvantageous in the case of very valuable cell cultures which, forexample, produce specific antibodies, vaccines or messenger substances,such as interleukins etc., and are therefore of great commercial value.

Finally, the compounds of the formula I can be used as standards inexperiments, for example as HPLC standards or as standards for comparinganimal models, in relation to different aspartate protease inhibitors,for example in regard to the blood levels which can be achieved.

The compounds of the formula I can be administered alone or else incombination (as a fixed combination of appropriate preparations or as acombination of individual active compounds or individual preparationsadministered in chronologically staggered sequence) with othersubstances which are active against retroviruses, in particular HIV,such as HIV-1 or HIV-2, or salts thereof, provided at least onesalt-forming group is present; in particular together with inhibitors ofreverse transcriptase, especially nucleoside analogues, in particular3'-azido-3'-deoxythyimidine (=zidovudine=®RETROVIR, Burroughs-Wellcome),2',3'-dideoxycytidine (=zalcitabine=®HIVID, Hoffmann-LaRoche),2',3'-dideoxyinosine (=didanosine=®VIDEX, Bristol-Myers-Squibb) or(2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan--5-yl)-(1H)-pyrimidin-2-one(=lamivindine, Glaxo) or non-nucleoside analogues, such as11-cyclopropyl-5,11-dihydro-4-methyl-(6H)-dipyrido 3,2-b;2',3'-e!-1,4!diazepin-6-one; and in the first place with one or more (inparticular one or else two) other inhibitors of retroviral asparateproteases, in particular the aspartate proteases from HIV, such as HIV-1and HIV-2, in particular one or more (preferably one or two), inparticular

a) one of the inhibitors named in EP 0 346 847 (published on 20.12.1989)and EP 0 432 695 (published on 10.06.1991; corresponds to U.S. Pat. No.5,196,438, published on 23.03.1993), in particular the compound with thedesignation Ro 31-8959 (=saquinavir, lHoffmann-LaRoche) of the formula##STR4## b) one of the inhibitors named in EP 0 541 168 (published onMay 5, 1993; corresponds to U.S. Pat. No. 5,413,999), in particular thecompound with the designation L-735,524 (=indinavir=®CRIXIVAN; Merck &Co., Inc.) of the formula ##STR5## c) one of the inhibitors named in EP0486 948 (published on May 27, 1992; corresponds to U.S. Pat. No.5,354,866), in particular the compound with the designation ABT-538(Abbott) of the formula ##STR6## d) the compound with the designationKVX-478 (or VX-478 or 141W94; Glaxo Wellcome, Vertex and KisseiPharmaceuticals) of the formula ##STR7## e) the compound with thedesignation AG-1343 (Agouron) of the formula ##STR8## f) the compoundwith the designation KNI-272 (Nippon Mining) of the formula ##STR9## g)the compound with the designation U-96988 (Upjohn) of the formula##STR10## and/or h) the compound with the designation BILA-2011 S(=palinavir; Boehringer-Ingelheim) of the formula ##STR11## or in eachcase a salt thereof, provided salt-forming groups are present.

Particularly when a compound of the formula I is combined with one ormore of the said inhibitors of retroviral aspartate proteases,synergistic effects can actually be observed, which is surprising sincethe inhibitors act on the same enzyme. The particular advantage of suchcombinations then resides in the decrease in the dosage quantities whichare required and in the more powerful anti-retroviral activity, whichcan simultaneously be achieved, of the active compounds when used incombination as compared with that which can be achieved using theindividual active compounds. This yields advantages with regard topossible side effects of the individual compounds and results in a lowernumber of viruses in the organism, so that the frequency of mutation canalso be lowered and hence the possibility of the development ofresistance can be reduced.

The activity of the combinations, and, in particular, the synergisticeffects, can be verified, for example, by means of experiments usingcell lines and peripheral mononuclear blood cells (lymphocytes andmonocytes).

CEM-SS cells (see Nara, P. L., et al., AIDS Res. Human Retroviruses 3,283-302 (1987), or Nara, P. L., et al., Nature 332, 469-70 (1988)) andthe permanently infected cell line H9/HTLV-IIIB NIH 1983 (H9/HIV-1/IIIBcells) of Gallo (see Popovic, M., et al., Science 224, 497-500 (1984);Popovic, M., et al., Lancet (1984) ii, 1472-3; or Ratner, L., et al.,Nature 313, 277-84 (1985)), for example, are employed for theexperiments using cell lines.

For the experiments using peripheral mononuclear blood cells, the cellsare isolated from the blood of healthy HIV-seronegative human subjectsusing a combination of leukaphoresis and counter-current centrifugalelutriation in accordance with known methods (see Alteri, E., et al.,Antimicrob. Agent Chemother. 37(10), 2087-92 (1993)).

The lymphocytotrophic isolate HIV-1/LAV (LAV.04/A.301), for example, isused as the virus (see Science 220, 868-71 (1983)).

The compounds to be tested, for example a compound of the formula I andone of the other inhibitors of retroviral aspartate proteases mentionedabove, for example saquinavir or indinavir, are dissolved in dimethylsulfoxide (=DMSO; 2 mM), with further dilutions being made usingcomplete tissue culture medium (see below). The final concentration offree DMSO is less than 0.5%.

The experiments for testing antiviral activity are carried out asfollows:

When using cell lines:

The cell lines are maintained in complete culture medium of thefollowing composition: RPMI 1640 (GIBCO, Paisley, Scotland),supplemented with 10% foetal calf serum (SEROMED, Berlin, Germany), 10mM 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid (=HEPES) and 2 mML-glutamine (AMIMED, Muttenz, Switzerland). The antiviral activity ofthe compounds is tested in a coculture system using CEM-SS cells andpermanently infected H9/HIV-1/IIIB cells. The test compounds are testedas individual substances or as a combination of two active substances indefined concentration ratios. H9/ HIV-1/IIIB cells are mixed, afterhaving been washed twice and having been suspended in fresh medium, withCEM-SS cells in a ratio of 1:50. 100 μl of the cell mixture aredispensed into each well of 96-well tissue culture plates with the wellsin each case containing 400 H9/HIV-1/IIIB cells and 2×10⁴ CEM-SS cells.Immediately after the cells have been dispensed, two-fold serialdilutions of the test compounds are added (100 μl per well) in each casein sets of six. Instead of this, 100 μl of medium are added to each wellfor the virus control (VC); CEM-SS cells on their own (withoutH9/HIV-1/IIIB cells) are used as the control (CC). The final volume is200 μl/well. After a 24 h incubation at 37° C. and in 5% CO₂, 150 μl ofeach supernatant is removed, without removing any cells, and replaced by150 μl of fresh medium which contains (or, in the case of the VC doesnot contain) fresh test substance or fresh test substances. 10 μlsamples of the culture supernatants are collected on day 4 and added toanother 96-well microtitre plate which, if required, is stored at -20°C. The virus production is determined as the virus-associated activityof the reverse transcriptase (RT) in accordance with the followingmethod, which has already been described above (see Alteri, E., et al.,Antimicrob. Agent Chemother. 37(10), 2087-92 (1993)):

When carrying out the measurement, 30 μl of reverse transcriptasecocktail are added to each well. The reverse transcriptase cocktailconsists of 50 mM Tris (α,α,α-tris(hydroxymethyl)methylamine, Ultra pur,Merck, Germany), pH 7.8; 75 mM KCl, 2 mM dithiothreitol, 5 mM MgCl₂ ;0.1% Nonidet P-40 (detergent; Sigma, Switzerland), 0.8 mM EDTA, 10 μg/mlpoly-A (Pharmacia, Uppsala, Sweden) and 0.16 μg/ml oligo(T)(=pdT(12-18), Pharmacia, Uppsala, Sweden) as template primer. Themixture is filtered through a 0.45 μm Acrodisc filter (Gelman SciencesInc., Ann Arbor, USA) and stored at -20° C. Prior to the test, 0.1%(v/v) alpha-³² P!dTTP is added to aliquots of the solution in order toachieve a final radioactivity of 10 μCi/ml.

After mixing, the plate is incubated at 37° C. for 1.5 h. 5 μl of thereaction mixture are transferred to DE81 paper (Whatman, one filter perwell). The dried filters are washed three times for 5 min with 300 mMNaCl/25 mM trisodium citrate and then once with ethanol, and air-driedonce again. The radioactivity on the filters is measured in a PackardMatrix 96-well counter (Packard, Zurich, Switzerland). Theantiretroviral effect is given as the % reduction in RT activity ascompared with the VC values.

When peripheral mononuclear blood cells are used:

The mixture of mononuclear cells (lymphocytes and monocytes), which isobtained as described above, is cultured, in the presence of 0.25 μg/mlphytohaemagglutinin (Wellcome Diagnostics, Temple Hill, Dartford,England), for two days in RPMI-1640 (GIBCO, Paisley, Scotland), 50 mU/mlpenicillin, 50 μg/ml streptomycin (ANIMED, Muttenz, Switzerland), 2 mML-glutamine (AMIMED, Muttenz, Switzerland) and 10 mM HEPES buffer(GIBCO, Paisley, Scotland). Successful activation is monitored bymeasuring the increase in cell size (scattergram, FCM analysis). Thecells are resuspended in complete medium containing 10% human AB serum(Sigma, St Louis, USA) and infected with HIV-1 for 6 h. After the viraladsorption, the cells are washed and resuspended in complete mediumwhich is supplemented with 100 U/ml human recombinant IL-2 (Genzyme,Cambridge, USA). 9×10⁴ cells are plated out per well (0.3 ml) in 96-wellplates having U-shaped well bottoms. The antiviral compounds are addedeither alone or in combination to sets of five cell cultures in eachcase (pentaplicates) directly following the infection. Two thirds of theculture medium with or without antiviral compound(s) are replaced everythree days. The test is concluded on day 13 after infection. Theprogress of the viral infection is measured by determining the RTactivity as described above for the cell lines.

In the groups of preferred compounds of the formula I which arementioned below, definitions of substituents from the abovementionedgeneral definitions can be employed in a meaningful manner, for exampleto replace more general definitions by more specific definitions or inparticular those definitions characterized as being preferred; in eachcase, those definitions are preferred which are characterized above asbeing preferred or as being examples.

A compound of the formula I (in particular of the formula I') ispreferred in which:

R₁ is an acyl radical selected from lower-alkoxy-lower-alkanoyl, suchas, in particular, lower-alkoxycarbonyl, especially tert-butoxycarbonyl,ethoxycarbonyl or methoxycarbonyl; lower-alkoxy-lower-alkanoyl (inparticular correspondingly substituted lower-alkoxycarbonyl) which issubstituted in the lower-alkoxy radical, once or more than once, byhalogen, in particular fluorine, by lower alkoxy or by pyrrolidinylwhich is unsubstituted or substituted by oxo, such as2,2,2-trifluoroethoxycarbonyl, 2-methoxyethoxycarbonyl, 2-methoxy-1(R,S)-methyl-ethoxycarbonyl, 1,1-dimethyl-2-methoxyethoxycarbonyl or2-oxopyrrolidin-5(S)-ylmethoxycarbonyl;N-lower-alkoxycarbonyl-piperidinyl-lower-alkanoyl, for example-carbonyl, such as N-ethoxycarbonyl-piperidin-4-ylcarbonyl;pyrrolidinyl-lower-alkanoyl, such as -carbonyl, which is substituted byhydroxyl on a carbon atom and/or by phenyl-lower-alkoxycarbonyl on thenitrogen atom and which is preferably in the (R) form, the (R,S) formor, in particular, the (S) form on the binding carbon atom, such as(L)-trans-4-hydroxyprolyl or(L)-N-benzyloxycarbonyl-trans-4-hydroxyprolyl;aminothiazolidinyl-lower-alkanoyl, for example -acetyl, such as2-amino-4-thiazolyl-acetyl; thiazolyl-lower alkanoyl, for example-carbonyl, such as thiazol-2-ylcarbonyl; indolyl-lower-alkanoyl, forexample -carbonyl, such as indol-2-ylcarbonyl;4H-1-benzopyranyl-lower-alkanoyl, for example -carbonyl, which issubstituted by oxo, such as 4-oxo-4H-1-benzopyran-2-ylcarbonyl;N-lower-alkyl-piperidinyloxy-lower-alkanoyl, for example -carbonyl, suchas N-methylpiperidin-4-yloxycarbonyl;tetrahydropyranyloxy-lower-alkanoyl, for example -propionyl or-carbonyl, such as 2(S)-(tetrahydropyran-4-yloxy)propionyl ortetrahydropyran-2(R,S)-yloxycarbonyl;tetrahydrofuranyloxy-lower-alkanoyl, for example -carbonyl, such astetrahydrofuran-3(S)-yloxycarbonyl; morpholinyl-lower-alkyl-benzoyl,such as 4-(morpholin-4-ylmethyl)benzoyl;lower-alkylpiperazinyl-pyridylcarbonyl, such asN-lower-alkylpiperazinyl-pyridylcarbonyl, in particular4-lower-alkyl-piperazin-1-yl-pyridylcarbonyl, for example 2- or3-(4-lower-alkyl such as methyl!-piperazin-1-yl)-pyridin-2-ylcarbonyl or-3-ylcarbonyl; phenyl-lower alkanoyl which is substituted by hydroxyl orlower alkyl, in particular methyl, preferably having in each case ahydroxyl substituent and a lower alkyl substituent, in particularhydroxyl and methyl, on the phenyl ring, in particular correspondingsubstituted benzoyl, such as 3-hydroxy-2-methyl-benzoyl; andphenylsulfonyl which is substituted by amino, nitro, amino and loweralkyl, such as methyl, or nitro and lower alkyl, such as methyl, such as4-nitrobenzenesulfonyl, 4-aminobenzenesulfonyl, 2-lower-alkyl(inparticular 2-methyl)-4-nitrobenzenesulfonyl or 4-amino-2-lower-alkyl (inparticular 2-methyl)-benzenesulfonyl;

is the residue, which is bonded via the carboxyl group, of an amino acidselected from valine, norvaline, leucine, isoleucine and norleucine and,in addition, from serine, homoserine, threonine, methionine, cysteine,phenylalanine, tyrosine, 4-aminophenylalanine, 4-chlorophenylalanine,4-carboxyphenylalanine, β-phenylserine, phenylglycine,α-naphthylalanine, cyclohexylalanine, cyclohexylglycine, typtophan,asparagine, aminomalonic acid monoamide, glutamic acid, glutamine,histidine, arginine, lysine, δ-hydroxylysine and omithine; with valinebeing particularly preferred; with the respective amino group(s) andother functional groups being free or (if possible) in salt form; andwith the said amino acid residues having asymmetric carbon atoms beingin the (D) form, the (L) form or the (D,L) form, preferably in the (L)form;

or is the residue, which is bonded via the carbonyl group, of one of theamino acids mentioned immediately above, which residue is N-acylated onthe amino nitrogen by one of the previously mentioned acyl radicals, inparticular a valine residue which is bonded via the carbonyl group andwhich is N-acylated by one of the previously mentioned acyl radicals, inparticular lower-alkoxy-lower-alkanoyl-valyl, such aslower-alkoxycarbonyl-valyl, for example methoxycarbonyl-valyl, orthiazolidinyl-valyl, in particular thiazolidin-4-yl-valyl which ispreferably in the (S) form, the (R,S) form or, in particular, the (R)form (=(L) form) at the 4 carbon atom of the thiazolidine ring; with thevalyl residue in each case preferably being in the (L) form;

R₂ and R₃ are selected, independently of each other, from cyclohexyl,cyclohexenyl, such as cyclohexen-1-yl, phenyl, biphenylyl, such as4-biphenylyl, (cyanophenyl)phenyl, such as 2'-cyanobiphenyl-4-yl,phenyl-lower-alkoxy-phenyl, in particular 4-phenyl-lower-alkoxy-phenyl,such as 4-(benzyloxy)-phenyl, difluorophenyl, in particular2,4-difluorophenyl, cyanophenyl, in particular 4-cyanophenyl,lower-alkoxyphenyl, such as 2-, 3- or 4-lower-alkoxyphenyl, for example4-isobutyloxyphenyl and, in particular, 2-, 3- and, especially,4-methoxyphenyl, tri-lower-alkoxy-phenyl, in particulartrimethoxyphenyl, for example having the lower-alkoxy substituents inthe 3,4,5 positions, such as in 3,4,5-trimethoxyphenyl, in the 2,4,5positions, such as in 2,4,5-trimethoxyphenyl, or in the 2,4,6 positions,such as in 2,4,6-trimethoxyphenyl, where the tri-lower-alkoxy- ormethoxy radicals are preferably asymmetrically bonded on the phenylring, primarily in the 2,3,4 positions, for example in2,3,4-trimethoxyphenyl, lower-alkoxy-lower-alkoxyphenyl, such as4-lower-alkoxy-lower-alkoxyphenyl, especially4-(2-methoxy-ethoxy)-phenyl, lower-alkylenedioxyphenyl, in which thelower-alkylenedioxy radical is bonded via its two oxygen atoms to twoadjacent carbon atoms of the phenyl ring, for examplemethylenedioxyphenyl, such as 3,4-methylenedioxyphenyl, andpyridyl-lower-alkoxyphenyl, in which pyridyl is bonded via a ring carbonatom, such as 4-(pyridin-2- or pyridin-3-yl-lower alkoxy) phenyl, inparticular pyridin-3-yl-lower-alkoxyphenyl, for examplepyridin-3-ylmethoxyphenyl; and, in addition, from4-lower-alkoxy-2-fluorophenyl, such as 4-methoxy-2-fluorophenyl,4-fluoro-2-lower-alkoxyphenyl, such as 4-fluoro-2-methoxyphenyl,4-lower-alkoxy-2-hydroxyphenyl, such as 4-methoxy-2-hydroxyphenyl,phenyl which is substituted not more than three times by lower alkyl,such as methyl, and lower alkoxy, such as methoxy, such as4-lower-alkoxy-2,3-di-lower-alkylphenyl, for example4-methoxy-2,3-dimethylphenyl, phenyl-lower-alkylphenyl, such as4-phenyl-lower-alkylphenyl, for example 4-(2-phenylethyl)-phenyl,fluorophenyl, such as 2-fluorophenyl, hydroxyphenyl, such as4-hydroxyphenyl, di-lower-alkoxyphenyl, in particular dimethoxyphenyl,for example 2,4-di-lower-alkoxyphenyl, such as 2,4-dimethoxyphenyl,3,4-di-lower-alkoxyphenyl, such as 3,4-dimethoxyphenyl,2,5-di-lower-alkoxyphenyl, such as 2,5-dimethoxyphenyl, or2,6-di-lower-alkoxyphenyl, such as 2,6-dimethoxyphenyl,tetrahydronaphthyl, in particular 5,6,7,8-tetrahydro-1-naphthyl,halonaphthyl, such as fluoronaphthyl, in particular 4-fluoronaphthyl,cyanonaphthyl, in particular 4-cyanonaphthyl, lower-alkoxyllaphthyl, inparticular 4-lower-alkoxynaphthyl, such as 4-methoxy-1-naphthyl, anddihalophenyl-lower-alkanesulfonylphenyl, in particulardichlorophenyl-lower-alkanesulfonylphenyl, such as4-(2,6-dichlorobenzylsulfonyl)phenyl; with the corresponding radicalspreferably being present in the combinations specified above as beingpreferred; in particular in one of the combinations specified aboveunder numbers 2), 4), 6), 8), 16), 24), 26), 27), 30) and 44), i.e. R₂=phenyl and R₃ =cyanophenyl (in particular 4-cyanophenyl); R₂ =phenyland R₃ =2,4-difluorophenyl; R₂ =phenyl and R₃ =4-lower-alkoxyphenyl, inparticular 4-methoxyphenyl; R₂ =4-(lower-alkoxy-lower-alkoxy)phenyl, inparticular 4-(2-methoxyethoxy)phenyl and R₃=4-(phenyl-lower-alkoxy)phenyl, in particular 4-(benzyloxy)phenyl; R₂=cyclohexyl and R₃ =4-lower-alkoxyphenyl, in particular 4-methoxyphenyl;R₂ =phenyl and R₃ =phenyl; R₂ =phenyl and R₃ =4-((pyridin-2-yl- or, inparticular, pyridin-3-yl)-lower alkoxy)phenyl, such as -methoxyphenyl;R₂ =phenyl and R₃ =3,4-lower-alkylenedioxyphenyl, in particular3,4-methylenedioxyphenyl; R₂ =cyclohexyl and R₃=4-(lower-alkoxy-lower-alkoxy)phenyl, in particular4-(2-methoxyethoxy)phenyl; or, in a particularly preferred manner, R₂=phenyl and R₃ =2,3,4-tri-lower-alkoxyphenyl, in particular2,3,4-trimethoxyphenyl;

R₄ is lower alkyl, preferably isopropyl, or, in addition, cyclohexyl orphenyl;

R₅ is lower alkyl, especially methyl or, in addition, ethyl or n-propyl;and

n is 2 or, preferably, is 1,

or a salt thereof, provided at least one salt-forming group is present.

A compound of the formula I is more strongly preferred in which

R₁ is an acyl radical selected from lower-alkoxy-lower-alkanoyl, suchas, in particular, lower-alkoxycarbonyl, especially tert-butoxycarbonyl,ethoxycarbonyl or methoxycarbonyl; lower-alkoxy-lower-alkanoyl (inparticular correspondingly substituted lower-alkoxycarbonyl) which issubstituted in the lower-alkoxy radical once or more than once byhalogen, in particular fluorine, by lower alkoxy or by pyrrolidinylwhich is unsubstituted or substituted by oxo, such as2,2,2-trifluoroethoxycarbonyl, 2-methoxyethoxycarbonyl or2-oxopyrrolidin-5(S)-ylmethoxycarbonyl;N-lower-alkoxycarbonyl-piperidinyl-lower-alkanoyl, for example-carbonyl, such as N-ethoxycarbonyl-piperidin-4-ylcarbonyl;pyrrolidinyl-lower-alkanoyl, such as -carbonyl, which is substituted byhydroxyl on a carbon atom and/or by phenyl-lower-alkoxycarbonyl on thenitrogen atom and which is preferably in the (R) form, the (R,S) formor, in particular, the (S) form at the binding carbon atom, such as(L)-trans-4-hydroxyprolyl or(L)-N-benzyloxycarbonyl-trans-4-hydroxyprolyl;aminothiazolidinyl-lower-alkanoyl, for example -acetyl, such as2-amino-4-thiazolyl-acetyl; thiazolyl-lower-alkanoyl, for example-carbonyl, such as thiazol-2-ylcarbonyl; indolyl-lower-alkanoyl, forexample -carbonyl, such as indol-2-ylcarbonyl;4H-1-benzopyranyl-lower-alkanoyl, for example -carbonyl, which issubstituted by oxo, such as 4-oxo-4H-1-benzopyran-2-ylcarbonyl;N-lower-alkyl-piperidinyloxy-lower-alkanoyl, for example -carbonyl, suchas N-methylpiperidin-4-yloxycarbonyl;tetrahydropyranyloxy-lower-alkanoyl, for example -propionyl or-carbonyl, such as 2(S)-(tetrahydropyran-4-yloxy)propionyl ortetrahydropyran-2(R,S)-yloxycarbonyl;tetrahydrofuranyloxy-lower-alkanoyl, for example -carbonyl, such astetrahydrofuran-3(S)-yloxycarbonyl; morpholinyl-lower-alkyl-benzoyl,such as 4-(morpholin-4-ylmethyl)-benzoyl; andlower-alkylpiperazinyl-pyridylcarbonyl, such asN-lower-alkylpiperazinyl-pyridylcarbonyl, in particular4-lower-alkyl-piperazin-1-yl-pyridylcarbonyl, for example 2- or3-(4-lower-alkyl such as methyl!-piperazin-1-yl-)-pyridin-2-ylcarbonylor -3-ylcarbonyl;

is the residue, which is bonded via the carboxyl group, of an amino acidselected from valine, norvaline, leucine, isoleucine and norleucine and,in addition, from serine, homoserine, threonine, methionine, cysteine,phenylalanine, tyrosine, 4-aminophenylalanine, 4-chlorophenylalanine,4-carboxyphenylalanine, β-phenylserine, phenylglycine,α-naphthylalanine, cyclohexylalanine, cyclohexylglycine, tryptophane,asparagine, aminomalonic acid monoamide, glutamic acid, glutamine,histidine, arginine, lysine, δ-hydroxylysine and ornithine; with valinebeing particularly preferred; with the respective amino group(s) andother functional groups being free or (if possible) in salt form; andwith the said amino acid residues having asymmetric carbon atoms beingin the (D) form, the (L) form or the (D,L) form, preferably in the (L)form;

or is the residue, which is bonded via the carbonyl group, of one of theamino acids mentioned immediately above, which residue is N-acylated onthe amino nitrogen by one of the previously mentioned acyl radicals, inparticular a valine residue which is bonded via the carbonyl group andis N-acylated by one of the previously mentioned acyl radicals, inparticular lower-alkoxy-lower-alkanoyl-valyl, such aslower-alkoxycarbonyl-valyl, for example methoxycarbonyl-valyl, orthiazolidinyl-valyl, in particular thiazolidin-4-yl-valyl, which ispreferably in the (S) form, the (R,S) form or, in particular, the (R)form (=(L) form) at the 4 carbon atom of the thiazolidine ring; with thevalyl residue in each case preferably being in the (L) form;

R₂ and R₃ are selected, independently of each other, from cyclohexyl,cyclohexenyl, such as cyclohexen-1-yl, phenyl,phenyl-lower-alkoxy-phenyl, in particular 4-phenyl-lower-alkoxyphenyl,such as 4-(benzyloxy)-phenyl, difluorophenyl, in particular2,4-difluorophenyl, cyanophenyl, in particular 4-cyanophenyl,lower-alkoxyphenyl, such as 2-, 3- or 4-lower-alkoxyphenyl, for example4-isobutyloxyphenyl and in particular 2-, 3- and, especially,4-methoxyphenyl, tri-lower-alkoxy-phenyl, in particulartrimethoxyphenyl, for example with the lower-alkoxy substituents in the3,4,5 positions, as in 3,4,5-trimethoxyphenyl, in the 2,4,5 positions,as in 2,4,5-trimethoxyphenyl, or in the 2,4,6 positions, as in2,4,6-trimethoxyphenyl, where the tri-lower-alkoxy or methoxy radicalsare preferably bonded asymmetrically on the phenyl ring, primarily inthe 2,3,4 positions, for example in 2,3,4-trimethoxyphenyl,lower-alkoxy-lower-alkoxyphenyl, such as4-lower-alkoxy-lower-alkoxyphenyl, especially4-(2-methoxyethoxy)-phenyl, lower-alkylenedioxyphenyl, in which thelower-alkylenedioxy radical is bonded via its two oxygen atoms to twoadjacent carbon atoms on the phenyl ring, for examplemethylenedioxyphenyl, such as 3,4-methylenedioxyphenyl, andpyridyl-lower-alkoxyphenyl, in which pyridyl is bonded via a ring carbonatom, such as 4-(pyridin-2- or pyridin-3-yl-lower-alkoxy)phenyl, inparticular pyridin-3-yl-lower-alkoxyphenyl, for examplepyridin-3-yl-methoxyphenyl; and, in addition, from4-lower-alkoxy-2-fluorophenyl, such as 4-methoxy-2-fluorophenyl,4-fluoro-2-lower-alkoxyphenyl, such as 4-fluoro-2-methoxyphenyl,4-lower-alkoxy-2-hydroxyphenyl, such as 4-methoxy-2-hydroxyphenyl,phenyl which is substituted not more than three times by lower alkyl,such as methyl, and lower alkoxy, such as methoxy, such as4-lower-alkoxy-2,3-di-lower-alkylphenyl, for example4-methoxy-2,3-dimethylphenyl, phenyl-lower-alkylphenyl, such as4-phenyl-lower-alkylphenyl, for example 4-(2-phenylethyl)phenyl,fluorophenyl, such as 2-fluorophenyl, hydroxyphenyl, such as4-hydroxyphenyl, di-lower-alkoxyphenyl, in particular dimethoxyphenyl,for example 2,4-di-lower-alkoxyphenyl, such as 2,4-dimethoxyphenyl,3,4-di-lower-alkoxyphenyl, such as 3,4-dimethoxyphenyl,2,5-di-lower-alkoxyphenyl, such as 2,5-dimethoxyphenyl, or2,6-di-lower-alkoxyphenyl, such as 2,6-dimethoxyphenyl,tetrahydronaphthyl, in particular 5,6,7,8-tetrahydro-1-naphthyl,halonaphthyl, such as fluoronaphthyl, in particular 4-fluoronaphthyl,cyanonaphthyl, in particular 4-cyanonaphthyl, lower-alkoxynaphthyl, inparticular 4-lower-alkoxynaphthyl, such as 4-methoxy-1-naphthyl, anddihalophenyl-lower-alkanesulfonylphenyl, in particulardichlorophenyl-lower-alkanesulfonylphenyl, such as4-(2,6-dichlorobenzylsulfonyl)phenyl; with the corresponding radicalspreferably being present in the combinations indicated above as beingpreferred; in particular in one of the combinations specified aboveunder numbers 2), 4), 6), 8), 16), 24), 26), 27), 30) and 44), i.e. R₂=phenyl and R₃ =cyanophenyl (in particular 4-cyanophenyl); R₂ =phenyland R₃ =2,4-difluorophenyl; R₂ =phenyl and R₃ =4-lower-alkoxyphenyl, inparticular 4-methoxyphenyl; R₂ =4-(lower-alkoxy-lower-alkoxy)phenyl, inparticular 4-(2-methoxyethoxy)phenyl, and R₃=4-(phenyl-lower-alkoxy)phenyl, in particular 4-(benzyloxy)phenyl; R₂=cyclohexyl and R₃ =4-lower-alkoxyphenyl, in particular 4-methoxyphenyl;R₂ =phenyl and R₃ =phenyl; R₂ =phenyl and R₃ =4-((pyridin-2-yl- or, inparticular pyridin-3-yl)-lower-alkoxy)phenyl, such as -methoxyphenyl; R₂=phenyl and R₃ =3,4-lower-alkylenedioxyphenyl, in particular3,4-methylenedioxyphenyl; R₂ =cyclohexyl and R₃=4-(lower-alkoxy-lower-alkoxy)phenyl, in particular4-(2-methoxyethoxy)phenyl; or, in particularly preferred manner, R₂=phenyl and R₃ =2,3,4-tri-lower-alkoxyphenyl, in particular2,3,4-trimethoxyphenyl;

R₄ is lower alkyl, preferably isopropyl, or, in addition, cyclohexyl orphenyl;

R₅ is lower alkyl, in particular methyl; and

n is 2 or, preferably is 1,

or a salt thereof, provided at least one salt-forming group is present.

A compound of the formula I (in particular I') is still more stronglypreferred in which

R₁ is selected from ethoxycarbonyl, tert-butoxycarbonyl,2,2,2-trifluoroethoxycarbonyl, 2-(methoxy)ethoxycarbonyl, 2-methoxy-1(R,S)-methylethoxycarbonyl, 1,1-dimethyl-2-methoxyethoxycarbonyl,5(S)-2-oxopyrrolidinylmethoxycarbonyl,1-ethoxycarbonylpiperidin-4-ylcarbonyl, trans-(L)-4-hydroxyprolyl,N-(benzyloxycarbonyl)-trans-(L)-4-hydroxyprolyl,(L)-thiazolidin-4-ylcarbonyl, indol-2-ylcarbonyl,4H-1-benzopyran-2-ylcarbonyl, N-methylpiperidinyloxycarbonyl,tetrahydropyran-2(R,S)-ylcarbonyl, O-(tetrahydropyran-4-yl)-(L)-lactoyl(=2(S)-(tetrahydropyran-4-yloxy)propionyl),3(S)-tetrahydrofuranyloxycarbonyl, 2-aminothiazol-4-ylacetyl,6-(4-methyl-piperazin-1-yl)pyridin-3-ylcarbonyl,4-(morpholin-4-ylmethyl)benzoyl, N-methoxycarbonyl-(L)-valyl, N-(L)-thiazolidin-4-ylcarbonyl!-(L)-valyl, 3-hydroxy-2-methylbenzoyl,4-nitrobenzenesulfonyl, 4-aminobenzenesulfonyl,2-methyl-4-nitrobenzenesulfonyl and 4-amino-2-methylbenzenesulfonyl;with tert-butoxycarbonyl being particularly preferred;

R₂ and R₃ are selected from cyclohexyl, cyclohexen-1-yl, phenyl,4-biphenylyl, 2'-cyanobiphenyl-4-yl, 4-(benzyloxy)-phenyl,2,4-difluorophenyl, 4-cyanophenyl, 2-, 3- or 4-methoxyphenyl,4-isobutyloxyphenyl, trimethoxyphenyl, for example having the methoxysubstituents in the 3,4,5 positions, as in 3,4,5-trimethoxyphenyl, inthe 2,4,5 positions, as in 2,4,5-trimethoxyphenyl or in the 2,4,6positions, as in 2,4,6-trimethoxyphenyl, where the methoxy radicals arepreferably bonded asymmetrically on the phenyl ring, primarily in the2,3,4 positions, for example in 2,3,4-trimethoxyphenyl,4-(2-methoxy-ethoxy)-phenyl, 3,4-methylenedioxyphenyl, and 4-(pyridin-2-or, in particular, pyridin-3-yl-methoxy)phenyl; and, in addition, from4-methoxy-2-fluorophenyl, 4-fluoro-2-methoxyphenyl,4-methoxy-2-hydroxyphenyl, 4-methoxy-2,3-dimethylphenyl,4-(2-phenylethyl)phenyl, 2-fluorophenyl, 4-hydroxyphenyl,dimethoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl,2,5-dimethoxyphenyl or 2,6-dimethoxyphenyl,5,6,7,8-tetrahydro-1-naphthyl, 4-fluoronaphthyl, 4-cyanonaphthyl,4-lower-alkoxynaphthyl and 4-(2,6-dichlorobenzylsulfonyl)phenyl, with R₂and R₃ preferably being present in the following combinations: R₂=4-benzyloxyphenyl and R₃ =4-benzyloxyphenyl; R₂ =phenyl and R₃=4-cyanophenyl; R₂ =phenyl and R₃ =2-fluorophenyl; R₂ =phenyl and R₃=2,4-difluorophenyl; R₂ =phenyl and R₃ =4-(2-phenylethyl)phenyl; R₂=phenyl and R₃ =4-(2,6-dichlorobenzylsulfonyl)-phenyl; R₂=4-(2-methoxyethoxy)phenyl and R₃ =4-benzyloxyphenyl; R₂=4-(2-methoxyethoxy)phenyl and R₃ =4-hydroxyphenyl; R₂=4-(2-methoxyethoxy)phenyl and R₃ =4-methoxyphenyl; R₂=4-(2-methoxyethoxy)phenyl and R₃ =4-(2-methoxyethoxy)-phenyl; R₂=4-benzyloxyphenyl and R₃ =4-methoxyphenyl; R₂ =4-hydroxyphenyl and R₃=4-methoxyphenyl; R₂ =4-methoxyphenyl and R₃ =4-methoxyphenyl; R₂=4-isobutyloxyphenyl and R₃ =4-methoxyphenyl; R₂ =4-methoxyphenyl and R₃=phenyl; R₂ =cyclohexyl and R₃ =4-methoxyphenyl; R₂ =phenyl and R₃=4-methoxy-2-fluorophenyl; R₂ =phenyl and R₃ =4-fluoro-2-methoxyphenyl;R₂ =phenyl and R₃ =4-methoxy-2-hydroxyphenyl; R₂ =4-methoxyphenyl and R₃=cyclohexyl; R₂ =4-methoxyphenyl and R₃ =cyclohexen-1-yl; R₂ =cyclohexyland R₃ =4-benzyloxyphenyl; R₂ =cyclohexyl and R₃ =4-hydroxyphenyl; R₂=cyclohexyl and R₃ =4-methoxyphenyl; R₂ =cyclohexyl and R₃=4-(2-methoxyethoxy)phenyl; R₂ =phenyl and R₃ =phenyl; R₂ =phenyl and R₃=4-benzyloxyphenyl; R₂ =phenyl and R₃ =4-hydroxyphenyl; R₂ =phenyl andR₃ =4-isobutoxyphenyl; R₂ =phenyl and R₃ =4-(pyridin-2-ylmethoxy)phenyl;R₂ =phenyl and R₃ =4-(pyridin-3-ylmethoxy)phenyl; R₂ =phenyl and R₃=4-methoxyphenyl; R₂ =phenyl and R₃ =3,4-methylenedioxyphenyl; R₂=phenyl and R₃ =3,4-dimethoxyphenyl; R₂ =phenyl and R₃ =3-methoxyphenyl;R₂ =phenyl and R₃ =2,3,4-trimethoxyphenyl; R₂ =phenyl and R₃=3,4,5-trimethoxyphenyl; R₂ =phenyl and R₃ =2,4-dimethoxyphenyl; R₂=phenyl and R₃ =2-methoxyphenyl; R₂ =phenyl and R₃=2,3-dimethyl-4-methoxyphenyl; R₂ =phenyl and R₃=2,4,5-trimethoxyphenyl; R₂ =phenyl and R₃ =2,4,6-trimethoxyphenyl; R₂=phenyl and R₃ =5,6,7,8-tetrahydro-1-naphthyl; R₂ =phenyl and R₃=2,5-dimethoxyphenyl; R₂ =phenyl and R₃ =2,6-dimethoxyphenyl; R₂ =phenyland R₃ =4-methoxy-1-naphthyl; R₂ =phenyl and R₃ =4-cyano-1-naphthyl; R₂=phenyl and R₃ =4-fluoro-1-naphthyl; R₂ =cyclohexyl and R₃=2,3,4-trimethoxyphenyl; R₂ =cyclohexyl and R₃=3,4-methylenedioxyphenyl; R₂ =cyclohexyl and R₃ =3,4-dimethoxyphenyl;R₂ =cyclohexyl and R₃ =3-methoxyphenyl; R₂ =cyclohexyl and R₃=3,4,5-trimethoxyphenyl; R₂ =cyclohexyl and R₃ =2,4-dimethoxyphenyl; R₂=cyclohexyl and R₃ =2-methoxyphenyl; R₂ =cyclohexyl and R₃=4-methoxy-2,3-dimethylphenyl; R₂ =cyclohexyl and R₃=2,4,5-trimethoxyphenyl; R₂ =cyclohexyl and R₃ =2,4,6-trimethoxyphenyl;R₂ =cyclohexyl and R₃ =5,6,7,8-tetrahydro-1-naphthyl; R₂ =cyclohexyl andR₃ =2,5-dimethoxyphenyl; R₂ =cyclohexyl and R₃ =2,6-dimethoxyphenyl; R₂=cyclohexyl and R₃ =4-methoxy-1-naphthyl; R₂ =cyclohexyl and R₃=4-cyano-1-naphthyl; R₂ =cyclohexyl and R₃ =4-fluoro-1-naphthyl; or(alternatively or additionally) R₂ =phenyl and R₃ =4-biphenylyl; R₂=4-benzyloxyphenyl and R₃ =4-biphenylyl; R₂ =4-hydroxyphenyl and R₃=4-biphenylyl; R₂ =4-methoxyphenyl and R₃ =4-biphenylyl; R₂ =phenyl andR₃ =2'-cyanobiphenyl-4-yl; R₂ =4-benzyloxyphenyl and R₃=2'-cyanobiphenyl-4-yl; R₂ =4-hydroxyphenyl and R₃=2'-cyanobiphenyl-4-yl; R₂ =4-methoxyphenyl and R₃=2'-cyanobiphenyl-4-yl; or R₂ =cyclohexyl and R₃ =2'-cyanobiphenyl-4-yl;with the following of these combinations being very particularlypreferred: R₂ =phenyl and R₃ =2,3,4-trimethoxyphenyl; R₂ =cyclohexyl andR₃ =2,3,4-trimethoxyphenyl; and, in addition, R₂ =phenyl and R₃=4-methoxyphenyl; or R₂ =cyclohexyl and R₃ =4-methoxyphenyl;

R₄ is isopropyl or, in addition, cyclohexyl or phenyl;

R₅ is methyl or, in addition, ethyl or n-propyl; and

n is 2 or, in particular, is 1;

or a salt thereof, provided at least one salt-forming group is present.

A compound of the formula I is much more strongly preferred in which

R₁ is selected from tert-butoxycarbonyl, 2,2,2-trifluoroethoxy-carbonyl,2-(methoxy)ethoxycarbonyl, 5(S)-2-oxo-pyrrolidinylmethoxycarbonyl,1-ethoxycarbonyl-piperidin-4-ylcarbonyl, trans-(L)-4-hydroxyprolyl,N-(benzyloxycarbonyl)-trans-(L)-4-hydroxyprolyl,(L)-thiazolidin-4-ylcarbonyl, indol-2-ylcarbonyl,4H-1-benzopyran-2-ylcarbonyl, N-methyl-piperidinyloxycarbonyl,tetrahydropyran-2(R,S)-ylcarbonyl, O-(tetrahydropyran-4-yl)-(L)-lactoyl(=2(S)-(tetrahydropyran-4-yloxy)propionyl),3(S)-tetrahydrofuranyloxycarbonyl, 2-amino-thiazol-4-ylacetyl,6-(4-methyl-piperazin-1-yl)-pyridin-3-ylcarbonyl,4-(morpholin-4-ylmethyl)-benzoyl, N-methoxycarbonyl-(L)-valyl and N-(L)-thiazolidin-4-ylcarbonyl!-(L)-valyl; with tert-butoxycarbonyl beingparticularly preferred;

R₂ and R₃ are selected from cyclohexyl, cyclohexen-1-yl, phenyl,4-(benzyloxy)-phenyl, 2,4-difluorophenyl, 4-cyanophenyl, 2-, 3- or4-methoxyphenyl, 4-isobutyloxyphenyl, trimethoxyphenyl, for example withthe methoxy substituents in the 3,4,5 positions, as in3,4,5-trimethoxyphenyl, in the 2,4,5 positions, as in2,4,5-trimethoxyphenyl or in the 2,4,6 positions, as in2,4,6-trimethoxyphenyl, where the methoxy radicals are preferably bondedasymmetrically on the phenyl ring, primarily in the 2,3,4 positions, forexample in 2,3,4-trimethoxyphenyl, 4-(2-methoxyethoxy)phenyl,3,4-methylenedioxyphenyl, and 4-(pyridin-2- or, in particular,pyridin-3-yl-methoxy)phenyl; and, in addition, from4-methoxy-2-fluorophenyl, 4-fluoro-2-methoxyphenyl,4-methoxy-2-hydroxyphenyl, 4-methoxy-2,3-dimethylphenyl,4-(2-phenylethyl)phenyl, 2-fluorophenyl, 4-hydroxyphenyl,dimethoxyphenyl, such as 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl,2,5-dimethoxyphenyl or 2,6-dimethoxyphenyl,5,6,7,8-tetrahydro-1-naphthyl, 4-fluoronaphthyl, 4-cyanonaphthyl,4-lower-alkoxynaphthyl and 4-(2,6-dichlorobenzylsulfonyl)phenyl, with R₂and R₃ preferably being present in the following combinations: R₂=4-benzyloxyphenyl and R₃ =4-benzyloxyphenyl; R₂ =phenyl and R₃=4-cyanophenyl; R₂ =phenyl and R₃ =2-fluorophenyl; R₂ =phenyl and R₃=2,4-difluorophenyl; R₂ =phenyl and R₃ =4-(2-phenylethyl)phenyl; R₂=phenyl and R₃ =4-(2,6-dichlorobenzylsulfonyl)-phenyl; R₂=4-(2-methoxyethoxy)phenyl and R₃ =4-benzyloxyphenyl; R₂=4-(2-methoxyethoxy)phenyl and R₃ =4-hydroxyphenyl; R₂=4-(2-methoxyethoxy)phenyl and R₃ =4-methoxyphenyl; R₂=4-(2-methoxyethoxy)phenyl and R₃ =4-(2-methoxyethoxy)-phenyl; R₂=4-benzyloxyphenyl and R₃ =4-methoxyphenyl; R₂ =4-hydroxyphenyl and andR₃ =4-methoxyphenyl; R₂ =4-methoxyphenyl and R₃ =4-methoxyphenyl; R₂=4-isobutyloxyphenyl and R₃ =4-methoxyphenyl; R₂ =4-methoxyphenyl and R₃=phenyl; R₂ =cyclohexyl and R₃ =4-methoxyphenyl; R₂ =phenyl and R₃=4-methoxy-2-fluorophenyl; R₂ =phenyl and R₃ =4-fluoro-2-methoxyphenyl;R₂ =phenyl and R₃ =4-methoxy-2-hydroxyphenyl; R₂ =4-methoxyphenyl and R₃=cyclohexyl; R₂ =4-methoxyphenyl and R₃ =Cyclohexen-1-yl; R₂ =cyclohexyland R₃ =4-benzyloxyphenyl; R₂ =cyclohexyl and R₃ =4-hydroxyphenyl; R₂=cyclohexyl and R₃ =4-methoxyphenyl; R₂ =cyclohexyl and R₃=4-(2-methoxyethoxy)phenyl; R₂ =phenyl and R₃ =phenyl; R₂ =phenyl and R₃=4-benzyloxyphenyl; R₂ =phenyl and R₃ =4-hydroxyphenyl; R₂ =phenyl andR₃ =4-isobutoxyphenyl; R₂ =phenyl and R₃ =4-(pyridin-2-ylmethoxy)phenyl;R₂ =phenyl and R₃ =4-(pyridin-3-ylmethoxy)phenyl; R₂ =phenyl and R₃=4-methoxyphenyl; R₂ =phenyl and R₃ =3,4-methylenedioxyphenyl; R₂=phenyl and R₃ =3,4-dimethoxyphenyl; R₂ =phenyl and R₃ =3-methoxyphenyl;R₂ =phenyl and R₃ =2,3,4-trimethoxyphenyl; R₂ =phenyl and R₃=3,4,5-trimethoxyphenyl; R₂ =phenyl and R₃ =2,4-dimethoxyphenyl; R₂=phenyl and R₃ =2-methoxyphenyl; R₂ =phenyl and R₃=2,3-dimethyl-4-methoxyphenyl; R₂ =phenyl and R₃=2,4,5-trimethoxyphenyl; R₂ =phenyl and R₃ =2,4,6-trimethoxyphenyl; R₂=phenyl and R₃ =5,6,7,8-tetrahydro-1-naphthyl; R₂ =phenyl and R₃=2,5-dimethoxyphenyl; R₂ =phenyl and R₃ =2,6-dimethoxyphenyl; R₂ =phenyland R₃ =4-methoxy-1-naphthyl; R₂ =phenyl and R₃ =4-cyano-1-naphthyl; R₂=phenyl and R₃ =4-fluoro-1-naphthyl; R₂ =cyclohexyl and R₃=3,4-methylenedioxyphenyl; R₂ =cyclohexyl and R₃ =3,4-dimethoxyphenyl;R₂ =cyclohexyl and R₃ =3-methoxyphenyl; R₂ =cyclohexyl and R₃=3,4,5-trimethoxyphenyl; R₂ =cyclohexyl and R₃ =2,4-dimethoxyphenyl; R₂=cyclohexyl and R₃ =2-methoxyphenyl; R₂ =cyclohexyl and R₃=2,3,4-trimethoxyphenyl; R₂ =cyclohexyl and R₃ =2,4,6-trimethoxyphenyl;R₂ =cyclohexyl and R₃ =5,6,7,8-tetrahydro-1-naphthyl; R₂ =cyclohexyl andR₃ =2,5-dimethoxyphenyl; R₂ =cyclohexyl and R₃ =2,6-dimethoxyphenyl; R₂=cyclohexyl and R₃ =4-methoxy-1-naphthyl; R₂ =cyclohexyl and R₃=4-cyano-1-naphthyl; or R₂ =cyclohexyl and R₃ =4-fluoro-1-naphthyl; withthe following of these combinations being very particularly preferred:R₂ =phenyl and R₃ =2,3,4-trimethoxyphenyl; R₂ =cyclohexyl and R₃=2,3,4-trimethoxyphenyl; R₂ =phenyl and R₃ =4-methoxyphenyl; or R₂=cyclohexyl and R₃ =4-methoxyphenyl; and, very particularly, thecombinations R₂ =phenyl and R₃ =2,3,4-tiimethoxyphenyl; and, inaddition, R₂ =cyclohexyl and R₃ =2,3,4-trimethoxyphenyl;

R₄ is isopropyl or, in addition, cyclohexyl or phenyl;

R₅ is ethyl or, in particular, methyl; and

n is 2 or, in particular, is 1;

or a salt thereof, provided at least one salt-forming group is present.

A compound of the formula I (in particular of the formula I') is verymuch preferred in which

R₁ is lower-alkoxycarbonyl or lower-alkoxycarbonyl which is substitutednot more than three times by halogen, in particular fluorine, and is, inparticular, tert-butoxycarbonyl or 2,2,2-trifluoroethoxycarbonyl;

R₂ and R₃ occur in the following combinations:

R₂ =phenyl and R₃ =cyanophenyl, in particular 4-cyanophenyl;

R₂ =phenyl and R₃ =difluorophenyl, in particular 2,4-difluorophenyl;

R₂ =phenyl and R₃ =4-lower-alkoxyphenyl, in particular 4-methoxyphenyl;

R₂ =4-(lower-alkoxy-lower-alkoxy)phenyl, in particular4-(2-methoxyethoxy)phenyl, and

R₃ =4-phenyl-lower-alkoxyphenyl, in particular 4-benzyloxyphenyl;

R₂ =cyclohexyl and R₃ =4-lower-alkoxyphenyl, in particular4-methoxyphenyl;

R₂ =phenyl and R₃ =phenyl; R₂ =phenyl and R₃=4-phenyl-lower-alkoxyphenyl, in particular 4-benzyloxyphenyl;

R₂ =phenyl and R₃ =4-(pyridin-3-yl-lower-alkoxy)phenyl, in particular4-(pyridin-3-ylmethoxy)phenyl;

R₂ =phenyl and R₃ =3,4-lower-alkylenedioxyphenyl, in particular3,4-methylenedioxyphenyl;

R₂ =phenyl and R₃ =2,3,4-tri-lower-alkoxyphenyl (particularlypreferred), in particular 2,3,4-trimethoxyphenyl (very particularlypreferred); or, in addition,

R₂ =cyclohexyl and R₃ =4-(lower-alkoxy-lower-alkoxy)phenyl, inparticular 4-(2-methoxyethoxy)phenyl;

R₄ is isopropyl;

R₅ is methyl; and

n is 1.

A compound of the formula I' is very particularly preferred in which

R₁ is lower-alkoxycarbonyl, in particular tert-butoxycarbonyl;

R₂ =phenyl and R₃ =4-lower-alkoxyphenyl, in particular 4-methoxyphenyl,or, preferably, 2,3,4-tri-lower-alkoxyphenyl, in particular2,3,4-trimethoxycarbonyl;

R₄ is isopropyl;

R₅ is methyl;

and n is 1.

Compounds of the formula I which are named in the examples, orpharmaceutically acceptable salts thereof, provided at least onesalt-forming group is present, are the most strongly preferred.

The compounds of the formula I, or salts of such compounds having atleast one salt-forming group, are obtained by processes which are knownper se, for example by

a) condensing an acid of the formula

    R.sub.1 --OH                                               (II)

or a reactive acid derivative thereof, in which R₁ has the same meaningsas R₁ in compounds of the formula I, with an amino compound of theformula ##STR12## (in particular of the formula ##STR13## or a reactivederivative thereof, in which n and the radicals have the meaningsspecified for compounds of the formula I, with free functional groups,with the exception of those participating in the reaction, beingpresent, if necessary, in protected form in the starting materials ofthe formulae II and III (or III'), and eliminating protective groupswhich are present, or

b) for preparing a compound of the formula ##STR14## (in particular ofthe formula ##STR15## in which B₁ is a bivalent residue of an aminoacid, as defined under formula I, which is bonded via the carbonyl group(to the binding nitrogen atom shown in formula Ia') and the amino group(to R₁ '), and R₁ ' is one of the radicals defined for R₁ under formulaI, apart from an unacylated or N-acylated amino acid residue as definedunder formula I, so that B₁ and R₁ ', together, are a residue, which isbonded via its carbonyl group, of a N-acylated amino acid, as definedfor R₁ under formula I, and n and the remaining radicals have themeanings specified for compounds of the formula I, condensing acarboxylic acid of the formula

    R.sub.1 '--OH                                              (IV)

or a reactive acid derivative thereof, in which R₁ ' can be a radical asdefined for R₁ in compounds of the formula I apart from a residue of anunacylated or N-acylated amino acid which is bonded via its carbonylgroup, with an amino compound of the formula ##STR16## (in particular ofthe formula ##STR17## or a reactive derivative thereof, in which B₁ hasthe meanings specified immediately above and n and the remainingradicals have the meanings specified for compounds of the formula I,with free functional groups, with the exception of those participatingin the reaction, being present, if necessary, in protected form in thestarting materials of the formulae IIIa (or IIIa') and IV, andprotective groups which are present being eliminated, or

c) condensing a carboxylic acid of the formula ##STR18## (in particularof the formula ##STR19## or a reactive derivative thereof, in which theradicals have the meanings specified for compounds of the formula I,with an amino compound of the formula ##STR20## (in particular of theformula ##STR21## or a reactive derivative thereof, in which n and theradicals have the meanings specified for compounds of the formula I,with free functional groups, with the exception of those participatingin the reaction, being present, if necessary, in protected form in thestarting materials of the formulae V (or V') and VI (or VI'), andprotective groups which are present being eliminated, or

d) condensing a carboxylic acid of the formula ##STR22## (in particularof the formula ##STR23## or a reactive derivative thereof, in which theradicals have the meanings specified for compounds of the formula I,with an amino compound of the formula ##STR24## or a reactive derivativethereof, in which n and R₅ have the meanings specified for compounds ofthe formula I, with free functional groups, with the exception of thoseparticipating in the reaction, being present, if required, in protectedform in the starting materials of the formulae VII (or VII') and VIII,and protective groups which are present being eliminated if desired, or

e) either

(i) etherifying a hydroxy compound of the formula ##STR25## (inparticular of the formula ##STR26## or its alcoholate salt, in which nand the radicals have the meanings specified for compounds of theformula I, with a compound of the formula

    W.sub.1 --R.sub.6                                          (X),

in which R₆ has the meanings specified for compounds of the formula Iand W₁ is a leaving group, or

(ii) etherifying a reactive derivative of the hydroxy compound of theformula IX (or IX') with a compound of the formula

    HO--R.sub.6                                                (Xa),

or its alcoholate salt, in which R₆ is defined as immediately above,with free functional groups, with the exception of those participatingin the reaction, being present, if necessary, in protected form in thestarting materials of the formulae IX (or IX'), X and Xa, and protectivegroups which are present being eliminated, or

f) eliminating protective groups which are present in a compound of theformula I (in particular I'), in which the substituents are as definedabove, with the proviso that in the compound of the formula I concernedat least one functional group is protected by protective groups,

with it being possible, in the specified process steps a) to f), if notalready specifically mentioned, for starting materials also to beemployed in the form of salts, provided salt-forming groups are present,

and/or, if desired, a compound of the formula I (or I'), which isobtained by one of the abovementioned processes a) to f) and which hasat least one salt-forming group, into its salt, and/or converting anobtainable salt into the free compound or into another salt, and/orresolving isomeric mixtures, which may be obtainable, of compounds ofthe formula I (or I'), and/or transforming a novel compound of theformula I (or I') into another novel compound of the formula I (or I').

The above-defined processes are described in more detail below:

In the description of the respective process steps, the radicals R₁, R₂,R₃, R₄ and R₅, and n have, both above and below, the meanings specifiedfor compounds of the formula I, unless otherwise indicated.

In each case, the preparation of compounds of the formula ##STR27## inwhich n and the radicals have the meanings specified for compounds ofthe formula I, is preferred when preparing compounds of the formula I.

In the respective processes, the compounds of the apostrophe-labelledformulae I', Ia', III', IIIa', V', VI', VII' and IX', having thestereospecificity indicated, are particularly preferred as compared withthe corresponding compounds without an indicated stereospecificity andwith the formulae I, Ia, II, IIIa, V, VI, VII and IX; the correspondingcompound mixtures, in which the carbon atoms (in the given sequenceC(5), C(2) and C(4)) carrying the radical R₂ --CH₂ --, the radical R₃--CH₂ -- and the OH located between them are in the (2R,4S,5S)configuration and the (2S,4R,5R) configuration and are in each case lesspreferred than the compounds labelled with an apostrophe but morestrongly preferred than the corresponding compounds without anyindicated stereospecificity.

In that which follows, preferably the corresponding compound mixtureshaving the (2R,4S,5S) configuration and the (2S,4R,5R) configuration or,in particular the compounds of the formulae which in each casecorrespond and which are labelled with an apostrophe can in each case beemployed in place of the compounds of the formulae I, Ia, III, IIIa, V,VI, VII and IX, provided this is chemically meaningful; this alsoapplies to the section on additional process measures and startingmaterials.

Process a) (preparation of an amide bond)

In starting materials of the formulae II and III, functional groups,with the exception of the groups which are to take part in the reactionor do not react under the reaction conditions, are, independently ofeach other, protected by protective groups.

Protective groups for functional groups in starting materials whosereaction is to be avoided, in particular carboxyl, amino, hydroxyl andmercapto groups, include, in particular, those protective groups(conventional protecting groups) which are customarily used in thesynthesis of peptide compounds or else of cephalosporins andpenicillins, and also nucleic acid derivatives and sugars. Theseprotective groups can already be present in the precursors and areintended to protect the functional groups concerned against unwantedside reactions such as acylations, etherifications, esterifications,oxidations, solvolysis, etc. In certain cases, the protective groupscan, in addition to this, have the effect of making the course ofreactions selective, for example stereoselective. It is characteristicof protective groups that they are easily detachable, i.e. withoutundesirable side reactions, for example solvolytically, reductively,photolytically or else enzymically, for example under physiologicalconditions as well, and that they are not present in the end products.Compounds of the formula I which possess protected functional groups,whose protective groups are detachable under physiological conditions,can have a higher degree of metabolic stability, or pharmacodynamicproperties which are otherwise improved, as compared with thecorresponding compounds having free functional groups.

The protection of functional groups by such protective groups, theprotective groups themselves, and also the reactions for eliminatingthem, are described, for example, in standard works such as J. F. W.McOmie, "Protective Groups in Organic Chemistry", Plenum Press, Londonand New York 1973, in Th. W. Greene, "Protective Groups in OrganicSynthesis", Wiley, New York 1981, in "The Peptides"; Volume 3 (E. Grossand J. Meienhofer, editors), Academic Press, London and New York 1981,in "Methoden der organischen Chemie" (Methods of Organic Chemistry),HoubenWeyl, 4th Edition, Volume 15/I, Georg Thieme Verlag, Stuttgart1974, in H. -D. Jakubke and H. Jescheit, "Aminosauren, Peptide,Proteine" (Amino Acids, Peptides and Proteins), Verlag Chemie, Weinheim,Deerfield Beach and Basel 1982, and in Jochen Lehmann, "Chemie derKohlenhydrate: Monosaccharide und Derivate" (Chemistry of theCarbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag,Stuttgart 1974.

A carboxyl group is, for example, protected as an ester group which canbe selectively cleaved under mild conditions. A carboxyl group which isprotected in esterified form is primarily esterified with a lower alkylgroup which is preferably branched in the 1 position of the lower alkylgroup or is substituted by suitable substituents in the 1 or 2 positionof the lower alkyl group.

A protected carboxyl group which is esterified with a lower alkyl groupis, for example, methoxycarbonyl or ethoxycarbonyl.

A protected carboxyl group which is esterified with a lower alkyl groupwhich is branched in the 1 position of the lower alkyl group is, forexample, tert-lower-alkoxycarbonyl, for example tert-butoxycarbonyl.

A protected carboxyl group which is esterified with a lower alkyl groupwhich is substituted in the 1 or 2 position of the lower alkyl group bysuitable substituents is, for example, 1-aryl-lower-alkoxycarbonyl, suchas arylmethoxycarbonyl, having one or two aryl radicals, in which arylis phenyl which is unsubstituted or is substituted once, twice or threetimes by, for example, lower alkyl, for example tert-lower-alkyl, suchas tert-butyl, lower alkoxy, for example methoxy, hydroxyl, halogen, forexample chlorine, and/or nitro, for example benzyloxycarbonyl,benzyloxycarbonyl which is substituted by the said substituents, forexample 4-nitrobenzyloxycarbonyl or 4-methoxybenzyloxycarbonyl,diphenylmethoxycarbonyl or diphenylmethoxycarbonyl which is substitutedby the said substituents, for exampledi-(4-methoxyphenyl)methoxycarbonyl, and, in addition, carboxyl which isesterified with a lower alkyl group, where the lower alkyl group issubstituted in the 1 or 2 position by suitable substituents, such as1-lower-alkoxy-lower-alkoxycarbonyl, for example methoxymethoxycarbonyl,1-methoxyethoxycarbonyl or 1-ethoxyethoxycarbonyl,1-lower-alkylthio-lower-alkoxycarbonyl, for example1-methylthiomethoxycarbonyl or 1-ethylthioethoxycarbonyl,aroylmethoxycarbonyl, in which the aroyl group is benzoyl which isunsubstituted or substituted, for example, by halogen, such as bromine,for example phenacyloxycarbonyl, 2-halo-lower-alkoxycarbonyl, forexample 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or2-iodethoxycarbonyl, and also 2-(trisubstitutedsilyl)-lower-alkoxycarbonyl, in which the substituents, independently ofeach other, are in each case an aliphatic, araliphatic, cycloaliphaticor aromatic hydrocarbon radical which is unsubstituted or substituted,for example, by lower alkyl, lower alkoxy, aryl, halogen and/or nitro,for example lower alkyl which is unsubstituted or substituted as above,phenyl-lower alkyl, cycloalkyl or phenyl, for example2-tri-lower-alkylsilyl-lower-alkoxycarbonyl, such as2-tri-lower-alkylsilylethoxycarbonyl, for example2-trimethylsilylethoxycarbonyl or2-(di-n-butylmethylsilyl)ethoxycarbonyl, or2-triarylsilylethoxycarbonyl, such as triphenylsilylethoxycarbonyl.

A carboxyl group can also be protected as an organic silyloxycarbonylgroup. An organic silyloxycarbonyl group is, for example, atri-lower-alkylsilyloxycarbonyl group, for exampletrimethylsilyloxycarbonyl. The silicon atom of the silyloxycarbonylgroup can also be substituted by two lower alkyl, for example methyl,groups, and an amino or carboxyl group of a second molecule of theformula I. Compounds possessing such protective groups can be prepared,for example, using corresponding tri-lower-alkylhalosilanes, such astert-butyldimethylchlorosilane, as silylating agents.

A carboxyl group is also protected in the form of an internal ester witha hydroxyl group which is present in the molecule at a suitabledistance, for example in the γ position with regard to the carboxylgroup, i.e. in the form of a lactone, preferably a γ-lactone.

A protected carboxyl group is preferably tert-lower-alkoxycarbonyl, forexample tert-butoxycarbonyl, benzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl ordiphenylmethoxycarbonyl, or a protected carboxyl group in the form of alactone, in particular a γ-lactone.

A protected amino group is protected by an amino protecting group, forexample in the form of an acylamino, arylmethylamino, etherifiedmercaptoamino, 2-acyl-lower-alk-1-enylamino or silylamino group, or asan azido group.

In an acylamino group, acyl is, for example, the acyl radical of anorganic carboxylic acid having, for example, up to 18 carbon atoms, inparticular of a lower-alkanecarboxylic acid which is unsubstituted orsubstituted, for example, by halogen or aryl, or of benzoic acid whichis unsubstituted or substituted, for example, by halogen, lower alkoxyor nitro, or, preferably, of a carbonic acid semiester. Such acyl groupsare, preferably, lower alkanoyl, such as formyl, acetyl, propionyl orpivaloyl, halo-lower-alkanoyl, for example 2-haloacetyl, such as2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloroacetyl,benzoyl which is unsubstituted or substituted, for example, by halogen,lower alkoxy or nitro, such as benzoyl, 4-chlorobenzoyl,4-methoxybenzoyl or 4-nitrobenzoyl, lower-alkoxycarbonyl,lower-alkoxycarbonyl which is preferably branched in the 1 position ofthe lower-alkyl radical or is suitably substituted in the 1 or 2position, for example tert-lower-alkoxycarbonyl, such astert-butoxycarbonyl, 1-aryl-lower-alkoxycarbonyl, such asarylmethoxycarbonyl, having one, two or three aryl radicals which arephenyl which is unsubstituted or substituted once or more than once by,for example, lower alkyl, in particular tert-lower-alkyl, such astert-butyl, lower alkoxy, such as methoxy, hydroxyl, halogen, such aschlorine, and/or nitro, for example benzyloxycarbonyl,4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl,9-fluorenylmethoxycarbonyl or di-(4-methoxyphenyl)methoxycarbonyl,aroylmethoxycarbonyl, in which the aroyl group is benzoyl which isunsubstituted or preferably substituted, for example, by halogen, suchas bromine, for example phenacyloxycarbonyl,2-halo-lower-alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl,2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, 2-(tri-substitutedsilyl)-lower-alkoxycarbonyl, for example2-tri-lower-alkylsilyl-lower-alkoxycarbonyl such as2-trimethylsilylethoxycarbonyl or2-(di-n-butylmethylsilyl)ethoxycarbonyl, ortriarylsilyl-lower-alkoxycarbonyl, for example2-triphenylsilylethoxycarbonyl.

In an arylmethylamino group, for example a mono-, di- or, in particular,tri-arylmethylamino group, the aryl radicals are, in particular, phenylradicals which are unsubstituted or substituted. Examples of such groupsare benzyl-, diphenylmethyl- or, in particular, trityl-amino.

In an etherified mercaptoamino group, the mercapto group is primarilypresent as substituted arylthio or aryl-lower-alkylthio in which arylis, for example, phenyl which is unsubstituted or substituted, forexample, by lower alkyl, such as methyl or tert-butyl, lower alkoxy,such as methoxy, halogen, such as chlorine, and/or nitro, for example4-nitrophenylthio.

In a 2-acyl-lower-alk-1-enyl radical which can be used as an aminoprotective group, acyl is, for example, the corresponding radical of alower-alkanecarboxylic acid, of a benzoic acid which is unsubstituted orsubstituted, for example, by lower alkyl, such as methyl or tert-butyl,lower alkoxy, such as methoxy, halogen, such as chlorine, and/or nitro,or, in particular, of a carbonic acid semiester, such as a carbonic acidlower-alkyl semiester. Corresponding protective groups are, primarily,1-lower-alkanoyl-lower-alk-1-en-2-yl, for example1-lower-alkanoyl-prop-1-en-2-yl, such as 1-acetyl-prop-1-en-2-yl, orlower-alkoxycarbonyl-lower-alk-1-en-2-yl, for examplelower-alkoxycarbonyl-prop-1-en-2-yl, such as1-ethoxycarbonyl-prop-1-en-2-yl.

A silylamino group is, for example, a tri-lower-alkylsilylamino group,for example trimethylsilylamino or tert-butyldimethylsilylamino. Thesilicon atom of the silylamino group can also only be substituted by twolower alkyl groups, for example methyl groups, and the amino group orcarboxyl group of a second molecule of the formula I. Compounds havingsuch protective groups can be prepared, for example, using thecorresponding chlorosilanes, such as tert-butyldimethylchlorosilane, assilating agents.

An amino group can also be protected by conversion into the protonatedform; suitable corresponding anions are primarily those of stronginorganic acids, such as of sulfuric acid, phosphoric acid or hydrohalicacids, for example the chlorine or bromine anion, or of organic sulfonicacids, such as p-toluenesulfonic acid.

Preferred amino protective groups are lower-alkoxycarbonyl,phenyl-lower-alkoxycaitbonyl, fluorenyl-lower-alkoxycarbonyl,2-lower-alkanoyl-lower-alk-1-en-2-yl orlower-alkoxycarbonyl-lower-alk-1-en-2-yl, especially tert-butoxycarbonylor benzyloxycarbonyl.

A hydroxyl group can, for example, be protected by an acyl group, forexample lower alkanoyl which is unsubstituted or substituted by halogen,such as chlorine, such as acetyl or 2,2-dichloroacetyl, or, inparticular, by an acyl radical, which is specified for protected aminogroups, of a carbonic acid semiester. A hydroxyl group can also beprotected by tri-lower-alkylsilyl, for example trimethylsilyl,triisopropylsilyl or tert-butyldimethylsilyl, a readily detachableetherifying group, for example an alkyl group, such as tert-lower-alkyl,for example tert-butyl, an oxa- or a thia-aliphatic or -cycloaliphatic,in particular 2-oxa- or 2-thia-aliphatic or -cycloaliphatic, hydrocarbonradical, for example 1-lower-alkoxy-lower-alkyl or1-lower-alkylthio-lower-alkyl, such as methoxymethyl, 1-methoxymethyl,1-ethoxymethyl, methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl,or 2-oxa- or 2-thia-cycloalkyl having 5-7 ring atoms, such as2-tetrahydrofuryl or 2-tetrahydropyranyl, or a corresponding thiaanalogue, and also by 1-phenyl-lower-alkyl, such as benzyl,diphenylmethyl or trityl, with it being possible for the phenyl radicalsto be substituted, for example, by halogen, for example chlorine, loweralkoxy, for example methoxy, and/or nitro. A preferred hydroxylprotective group is, for example, 2,2,2-trichloroethoxycarbonyl,4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl, benzyl or trityl.

Two hydroxyl groups, in particular adjacent hydroxyl groups, which arepresent in a molecule, or an adjacent hydroxyl group and amino group,can, for example, be protected by bivalent protective groups, such as amethylene group which is preferably substituted, for example by one ortwo lower alkyl radicals or oxo, for example by unsubstituted orsubstituted alkylidene, for example lower alkylidene, such asisopropylidene, cycloalkylidene, such as cyclohexylidene, a carbonylgroup or benzylidene.

A hydroxyl group which is located adjacent to a carboxyl group can beprotected by the formation of an internal ester (lactone), in particularof a γ-lactone.

Preferably, a protected hydroxyl group is protected bytri-lower-alkylsilyl or as a lactone, in particular bytert-butyldimethylsilyl or as a γ-lactone.

A mercapto group, for example in cysteine, can be protected, inparticular, by S-alkylation with unsubstituted or substituted alkylradicals, silylation, thioacetal formation, S-acylation or by theformation of asymmetric disulfide groups. Preferred mercapto protectivegroups are, for example, benzyl which is unsubstituted or substituted inthe phenyl radical, for example by methoxy or nitro, such as4-methoxybenzyl, diphenylmethyl which is unsubstituted or substituted inthe phenyl radical, for example by methoxy, such asdi-(4-methoxyphenyl)methyl, Triphenylmethyl, Pyridyldiphenylmethyl,trimethylsilyl, benzylthiomethyl, tetrahydropyranyl, acylaminomethyl,such as acetamidomethyl, iso-butyrylacetamidomethyl or2-chloroacetamidomethyl, benzoyl, benzyloxycarbonyl or alkyl-, inparticular lower-alkylaminocarbonyl, such as ethyl-aminocarbonyl, andalso lower-alkylthio, such as S-ethylthio or S-tert-butylthio, orS-sulfo.

Within the meaning of this application, a polymeric support, as issuitable, for example, for the Merrifield synthesis, and which is boundin an easily detachable manner to the functional group to be protected,for example a carboxyl group, is also expressly understood to be aprotective group, for example a carboxyl protective group. A suitablepolymeric support of this nature is, in particular, a polystyrene resinwhich is weakly cross-connected by copolymerization with divinylbenzeneand which carries suitable bridge members for the reversible binding.

The acids of the formula II are carboxylic acids or sulfonic acids andeither have a free carboxylic group or free sulfo group or are presentas a reactive derivative thereof, for example as an activated esterwhich is derived from the free carboxy or sulfo compound, as a reactiveanhydride, or, in addition, as a reactive cyclic amide. The reactivederivatives can also be formed in situ.

Activated esters of compounds of the formula II having a carboxyl groupare, in particular, esters which are unsaturated at the linking carbonatom of the esterifying radical, for example of the vinyl ester type,such as vinyl ester (obtainable, for example, by transesterifying acorresponding ester with vinyl acetate; method of the activated vinylester), carbamoyl esters (obtainable, for example, by treating thecorresponding acid with an isoxazolium reagent; 1,2-oxazolium method orWoodward method), or 1-lower-alkoxyvinyl ester (obtainable, for example,by treating the corresponding acid with a lower-alkoxyacetylene;ethoxyacetylene method), or esters of amidino type, such asN,N'-disubstituted amidinoesters (obtainable, for example, by treatingthe corresponding acid with a suitable N,N'-di-substituted carbodiimide,for example N,N'dicyclohexylcarbodiimide; carbodiimide method), orN,N-disubstituted amidinoesters (obtainable, for example, by treatingthe corresponding acid with a N,N-disubstituted cyanamide; cyanamidemethod), suitable aryl esters, in particular phenyl esters which aresubstituted by electron-attracting substituents (obtainable, forexample, by treating the corresponding acids with a suitably substitutedphenol, for example 4-nitrophenol, 4-methylsulfonylphenol,2,4,5-trichlorophenol, 2,3,4,5,6-pentachlorophenol or4-phenyldiazophenol, in the presence of a condensing agent, such asN,N'-dicyclohexylcarbodiimide; method of the activated aryl esters),cyanomethyl esters (obtainable, for example, by treating thecorresponding acid with chloroacetonitrile in the presence of a base;cyanomethyl ester method), thioesters, in particular phenylthioesters,which are unsubstituted or substituted, for example, by nitro(obtainable, for example, by treating the corresponding acid withthiophenols which are unsubstituted or substituted, for example, bynitro, inter alia using the anhydride method or carbodiimide method;method of the activated thiol esters), or, in particular, amino estersor amido esters (obtainable, for example, by treating the correspondingacid with a N-hydroxyamino compound or N-hydroxyamido compound, forexample N-hydroxysuccinimide, N-hydroxypiperidine, N-hydroxyphthalimide,N-hydroxy-5-norbornene-2,3-dicarboximide, 1-hydroxybenzotriazole or3-hydroxy-3,4-dihydro-1,2,3-benzotriazin-4-one, for example inaccordance with the anhydride method or carbodiimide method; method ofthe activated N-hydroxy esters). Internal esters, for exampleγ-lactones, can also be employed.

Anhydrides of acids can be symmetrical or, preferably, mixed anhydridesof these acids, for example anhydrides with inorganic acids, such asacid halides, in particular acid chlorides (obtainable, for example, bytreating the corresponding acid with thionyl chloride, phosphoruspentachloride or oxalyl chloride; acid chloride method), azides(obtainable, for example, from a corresponding acid ester via thecorresponding hydrazide and its treatment with nitrous acid; azidemethod), anhydrides with carbonic acid semiesters, for example carbonicacid lower-alkyl semiesters (obtainable, for example, by treating thecorresponding acid with lower-alkyl chloroformates, for example isobutylchloroformate, or with a1-lower-alkoxycarbonyl-2-lower-alkoxy-1,2-dihydroquinoline; method ofmixed O-alkylcarbonic acid anhydrides) or trichloromethyl carbonates(obtainable, for example, by treating the corresponding acid withbis(trichloromethyl)carbonate in ether/pyridine); anhydrides withdihalogenated, in particular dichlorinated, phosphoric acid (obtainable,for example, by treating the corresponding acid with phosphorusoxychloride; phosphorus oxychloride method), anhydrides with otherphosphoric acid derivatives (for example those which can be obtainedwith phenyl N-phenylphosphoramidochloridate or by reaction ofalkylphosphoric acid amides in the presence of sulfonic anhydridesand/or racemization-lowering additives, such as N-hydroxybenzotriazole,or in the presence of diethyl cyanophosphonates) or with phosphoric acidderivatives, or anhydrides with organic acids, such as mixed anhydrideswith organic carboxylic acids (obtainable, for example, by treating thecorresponding acid with a lower-alkane- or phenyl-lower-alkanecarbonylhalide which is unsubstituted or substituted, for example phenyl acetylchloride, pivaloyl chloride or trifluoroacetyl chloride; method of themixed carboxylic anhydrides) or with organic sulfonic acids (obtainable,for example, by treating a salt, such as an alkali metal salt, of thecorresponding acid with a suitable organic sulfonyl halide, such aslower-alkane- or aryl-, for example methane- or p-toluene-sulfonylchloride; method of the mixed sulfonic anhydrides) and also symmetricalanhydrides (obtainable, for example, by condensing the correspondingacid in the presence of a carbodiimide or of 1-diethylaminopropyne;method of the symmetrical anhydrides).

Suitable cyclic amides are, in particular, amides with five-membereddiazacycles of aromatic character, such as amides with imidazoles, forexample imidazole (obtainable, for example, by treating thecorresponding acid with N,N'-carbonyldiimidazole; imidazole method), orpyrazole, for example 3,5-dimethylpyrazole (obtainable, for example, viathe acid hydrazide by treating with acetylacetone; pyrazolide method).

As mentioned, derivatives of carboxylic acids which are used asacylating agents can also be formed in situ. Thus, N,N'-disubstitutedamidinoesters can be formed in situ by causing the mixture of thestarting material of the formula III and the acid of the formula II usedas acylating agent, in the presence of a suitable N,N'-disubstitutedcarbodiimide, for example N,N'-dicyclohexylcarbodiimide, to react, forexample in the presence of a suitable base, such as triethylamine,and/or a racemization-lowering additive, such as N-hydroxybenzotriazole.In addition, aminoesters or amidoesters of the acids used as acylatingagents can be formed in the presence of the starting material of theformula III which is to be acylated by reacting the mixture of thecorresponding acid and amino starting materials in the presence of aN,N'-disubstituted carbodiimide, for exampleN,N'-dicyclohexylcarbodiimide, and a N-hydroxyamine or N-hydroxyamide,for example N-hydroxysuccinimide, in the presence or absence of asuitable base, for example 4-dimethylaminopyridine. In addition,activation can be achieved in Situ by reacting withN,N,N',N'-tetraalkyluronium compounds, such as0-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate(preferably in the presence of a tertiary nitrogen base, in particularN-methylmorpholine). Phosphoric anhydrides of the carboxylic acids ofthe formula II can also be prepared in situ by reacting analkylphoshoric acid amide, such as hexamethylphosphoric triamide, in thepresence of a sulfonic anhydride, such as 4-toluenesulfonic anhydride,with a salt, such as a tetrafluoroborate, for example sodiumtetrafluoroborate, or with another derivative of hexamethylphosphorictriamide, such as benzotriazol-1-yloxytris(dimethylamino)-phosphoniumhexafluoride, preferably in the presence of a racemization-loweringadditive, such as N-hydroxybenzotriazole, and with or without a tertiarynitrogen base, such as N-methylmorpholine. It is also possible to carryout the reaction with di-lower-alkyl cyanophosphonates, such as diethylcyanophosphonate, in the presence of a tertiary nitrogen base, such astriethylamine. Finally, chlorocarbonic acid derivatives of thecarboxylic acids of the formula II can be prepared directly in situ bythe reaction of a corresponding alcohol with phosgene or an analoguethereof, such as triphosgene (=bis(trichloromethyl)carbonate) in thepresence or absence of a tertiary nitrogen base, such as triethylamine,and subsequently reacted with a compound of the formula III.

The amino group of compounds of the formula III, which participates inthe reaction, preferably carries at least one reactive hydrogen atom, inparticular when the carboxyl group reacting with it is present inreactive form; however, it can itself also be derivatized, for exampleby reaction with a phosphite, such as diethyl chlorophosphite,1,2-phenylene chlorophosphite, ethyl dichlorophosphite, ethylenechlorophosphite or tetraethyl pyrophosphite. A derivative of such acompound with an amino group is also, for example, a carbamoyl halide,with the amino group participating in the reaction being substituted byhalocarbonyl, for example chlorocarbonyl.

The condensation for preparing an amide bond can be carried out in amanner known per se, for example as described in standard works such as"Houben-Weyl, Methoden der organischen Chemie" (Methods of OrganicChemistry), 4th Edition, Volume 15/II (1974), Volume IX (1955) Volume E11 (1985), Georg Thieme Verlag, Stuttgart, "The Peptides" (E. Gross andJ. Meienhofer, editors), Volumes 1 and 2, Academic Press, London and NewYork, 1979/1980, or M. Bodansky, "Principles of Peptide Synthesis",Springer-Verlag, Berlin 1984.

The condensation of a free carboxylic acid with the corresponding aminecan preferably be carried out in the presence of one of the customarycondensing agents. Examples of customary condensing agents arecarbodiimides, for example diethyl-, dipropyl-,N-ethyl-N'-(3-dimethylatninopropyl)carbodiimide or, in particular,dicyclohexylcarbodiimide, and, in addition, suitable carbonyl compounds,for example carbonylimidazole, 1,2-oxazolium compounds, for example2-ethyl-5-phenyl-1,2-oxazolium-3'-sulfonate and2-tert-butyl-5-methylisoxazolium perchlorate, or a suitable acylaminocompound, for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline,N,N,N',N'-tetraalkyluronium compounds, such asO-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate,and, in addition, activated phosphoric acid derivatives, for examplediphenylphosphoryl azide, diethylphosphoryl cyanide (=diethylcyanophosphonate), phenyl-N-phenylphosphoroamidochloridate,bis(2-oxo-3-oxazolidinyl)phosphinic chloride or1-benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate.

If necessary or desired, an organic base is added, preferably atri-substituted nitrogen base, for example a tri-lower-alkylamine, forexample with bulky radicals, for example ethyl diisopropylamine, or withunbranched radicals, such as, in particular, triethylamine, and/or aheterocyclic base, for example pyridine, 4-dimethylaminopyridine or,preferably N-methylmorpholine. The base can also be bonded to apolymeric support, for example polystyrene, for example as a "polyhunigbase" (=diisopropylaminomethylpolystyrene).

Racemization-lowering reagents, such as N-hydroxybenzotriazole, can alsobe added, possibly also in combination with organic bases, as definedimmediately above.

The condensation of activated esters, reactive anhydrides or reactivecyclic amides with the corresponding amines is customarily carried outin the presence of an organic base, for example simpletri-lower-alkylamines, for example triethylamine or tributylamine,polyhunig base or one of the abovementioned organic bases. It ispossible, if desired, additionally to use a condensing agent as well, asdescribed for free carboxylic acids.

The condensation of acid anhydrides with amines can, for example, alsobe effected in the presence of inorganic carbonates, for exampleammonium or alkali metal carbonates or hydrogen carbonates, such assodium or potassium carbonate or hydrogen carbonate (customarilytogether with a sulfate).

Carbonyl chlorides or 4-nitrophenyl carbonates, and also thechlorocarbonic acid derivatives derived from the acid of the formula II,are preferably condensed with the corresponding amines in the presenceof an organic amine, for example the abovementionedtri-lower-alkylamines or heterocyclic bases, in the presence or absenceof a hydrogen sulfate.

The condensation is preferably carried out in inert, aprotic, preferablyanhydrous, solvents or solvent mixtures, for example in a carboxamide,for example formamide or dimethylformamide, a halogenated hydrocarbon,for example methylene chloride, carbon tetrachloride or chlorobenzene, aketone, for example acetone, a cyclic ether, for exampletetrahydrofuran, an ester, for example ethyl acetate, or a nitrile, forexample acetonitrile, or in a mixture thereof, if desired at decreasedor increased temperature, for example in a temperature range of fromabout -40° C. up to about +100° C., preferably from about -20° C. toabout +50° C., and without inert gas (=protective gas) or under an inertgas, for example nitrogen or argon, atmosphere.

Aqueous, for example alcoholic, solvents or solvent mixtures, forexample ethanol, or aromatic solvents, for example benzene or toluene,are also possible. A lower-alkanone, such as acetone, can also, ifdesired, be added in the presence of alkali metal hydroxides as bases.

The condensation can also be effected in accordance with the techniqueknown as solid-phase synthesis which goes back to R. Merrifield and isdescribed, for example, in Angew. Chem. 97, 801-812 (1985),Naturwissenschaften 71, 252-258 (1984) or in R. A. Houghten, Proc. Natl.Acad. Sci. USA 82, 5131-5135 (1985).

Many of the reaction types listed above for carboxylic acids of theformula II and analogous reactive sulfonic acid derivatives, also in thecase of compounds of the formula II having a sulfo group to be linked,can be used in an analogous manner for preparing sulfonamide compoundsof the formula I, in particular I'.

Thus, activated sulfonic esters, for example, can be employed, forexample the corresponding aryl esters which are substituted, inparticular, by nitro groups, such as 4-nitrophenyl esters, with it beingpossible also to employ the amine component of the formula III as analkali metal amide, for example alkali metal arylamide, such as sodiumanilineamide, or as an alkali metal salt of nitrogen-containingheterocycles, for example potassium pyrrolide.

Reactive anhydrides can also be employed, such as, for example, thecorresponding symmetrical (which can be prepared, for example, byreacting the alkanesulfonic silver salts with alkanesulfonyl chlorides)or, preferably, asymmetrical acid anhydrides, for example anhydrideswith inorganic acids, such as sulfonyl halides, in particular sulfonylchlorides (obtainable, for example, by reacting the correspondingsulfonic acid of the formula II with inorganic acid chlorides, forexample thionyl chloride or phosphorus pentachloride), with organiccarboxylic acids (obtainable, for example, by treating a sulfonyl halidewith the salt of a carboxylic acid, such as an alkali metal salt, in ananalogous manner to the abovementioned method of mixed carboxylicanhydrides), or azides (obtainable, for example, from a correspondingsulfonyl chloride and sodium azide or via the corresponding hydrazideand its treatment with nitrous acid in analogy with the abovementionedazide method).

The release of functional groups which are protected by protectivegroups in the resulting compounds of the formula I having protectedfunctions is effected using one or more of the methods specified underprocess f).

Process b) (preparation of an amide bond)

In starting materials of the formulae IIIa and IV, functional groups,with the exception of the groups which are to participate in thereaction or which do not react under the reaction conditions, areprotected, independently of each other, by protective groups.

The protective groups, the free carboxylic acids and their reactivederivatives, the free amines and their reactive derivatives and theprocesses used for the condensation are completely analogous to thosedescribed under process a) for the preparation of an amide bondproceeding from compounds of the formulae II and III, if the carboxylicacids of the formula IV are employed there in place of those of theformula II and the amino compounds of the formula IIIa are employed inplace of those of the formula III.

The release of functional groups which are protected by protectivegroups in the resulting compounds of the formula I having protectedfunctions is effected using one or more of the methods specified underprocess f).

Process c) (preparation of an amide bond)

In starting materials of the formulae V and VI, functional groups, withthe exception of the groups which are to participate in the reaction orwhich do not react under the reaction conditions, are protected,independently of each other, by protective groups.

The protective groups, the free carboxylic acids and their reactivederivatives, the free amines and their reactive derivatives and theprocesses used for the condensation are completely analogous to thosedescribed under process a) for the preparation of an amide bondproceeding from compounds of the formulae II and III, if the carboxylicacids of the formula V are employed there in place of those of theformula II and the amino compounds of the formula VI are employed inplace of those of the formula III.

In addition to the reactive derivatives in analogy with process a), areactive derivative of a carboxylic acid of the formula V can also bethe corresponding γ-lactone of the formula XXA ##STR28## (in particularof the formula XXA') ##STR29## in which the radicals R₁, R₂ and R₃ havethe meanings specified for compounds of the formula I. The reaction thenproceeds directly to yield the end product in the presence of an organicacid which is, if anything, mild, for example a substituted or(preferably) unsubstituted lower-alkanoic acid, such as trihaloaceticacid, for example trichloroacetic acid, or, in particular, acetic acid,or other organic acids of similar acidity, for example2-hydroxypyridine, at preferred temperatures of between 10 and 100° C.,in particular of between 60 and 100° C., in the presence or, preferably,in the absence of solvents, preferably while excluding the atmosphere,for example in bomb tubes. Preferably, the compound of the formula VI,in particular VI', is then employed in a slight excess, for example infrom 1.01-fold to 4-fold molar excess, in relation to the compound ofthe formula XXA, in particular XXA', with the, if anything, mild organicacid on the other hand preferably being employed in slight excess, inequimolar quantity or in slight deficit in relation to the compound ofthe formula VI, in particular VI', for example in a 0.3-fold to 2-foldmolar ratio.

The release of functional groups which are protected by protectivegroups in the resulting compounds of the formula I having protectedfunctions is effected using one or more of the methods specified underprocess f).

Process d) (preparation of an amide bond)

In starting materials of the formulae VII and VIII, functional groups,with the exception of the groups which are to participate in thereaction or which do not react under the reaction conditions, areprotected, independently of each other, by protective groups.

The protective groups, the free carboxylic acids and their reactivederivatives, the free amines and their reactive derivatives and theprocesses used for the condensation are completely analogous to thosedescribed under process a) for the preparation of an amide bondproceeding from compounds of the formulae II and III, if the carboxylicacids of the formula VII are employed there in place of those of theformula II and the amino compounds of the formula VIII are employed inplace of those of the formula III.

The release of functional groups which are protected by protectivegroups in the resulting compounds of the formula I having protectedfunctions is effected using one or more of the methods specified underprocess f).

Process e) (preparation of an ether bond--nucleophilic substitution)

In starting materials of the formulae IX, X and Xa, functional groups,with the exception of the groups which are to participate in thereaction or which do not react under the reaction conditions, areprotected, independently of each other, by protective groups.

The protective groups, and the methods for introducing them, correspondto those specified under process a).

In the nucleophilic substitution, either, in case (i), the compound ofthe formula IX has a free hydroxyl group which is to be etherified andW₁ in the compound of the formula X is a leaving group, or, in case(ii), the compound of the formula IX is in the form of a reactivederivative and is reacted with the hydroxyl group which is to beetherified. In this context, the hydroxyl group, which is to be reacted,of the respective hydroxyl compound is converted into its alcoholatesalt either in situ or in a previous, independent reaction. In analcoholate salt, the hydroxyl group (--OH) is present in anionic form(as --O.sup.⊖), with a suitable counterion principally being a metalcation, such as an alkali metal cation, for example IK.sup.⊕, Cs.sup.⊕or, in particular, Na.sup.⊕. A leaving group W₁ is, in particular, anucleofugic leaving group selected from hydroxyl which is esterifiedwith a strong inorganic or organic acid, such as hydroxyl which isesterified with a mineral acid, for example hydrohalic acid, such ashydrochloric, hydrobromic or hydriodic acid, or with a strong organicsulfonic acid such as a lower-alkanesulfonic acid which is unsubstitutedor substituted, for example, by halogen, such as fluorine, or anaromatic sulfonic acid, for example a benzenesulfonic acid which isunsubstituted or substituted by lower alkyl, such as methyl, halogen,such as bromine, and/or nitro, for example a methanesulfonic,p-brornotoluenesulfonic or p-toluenesulfonic acid, or hydroxyl which isesterified with hydrazoic acid. It is also possible to prepare thecompound concerned in situ by substituting another corresponding radicalW₁, for example of Cl, by another radical W₁, for example I (preferablyusing an alkali metal iodide, such as NaI) and subsequently continuingwith the reaction in the resulting reaction mixture.

In a reactive derivative of a compound of the formula IX, a leavinggroup, such as described immediately above for W₁, is present in placeof the hydroxyl group.

The etherification preferably takes place in the presence of arelatively mild base, such as an alkali metal carbonate, for examplesodium or potassium carbonate, of a strong base, for example ahydroxide-containing base, such as a metal hydroxide, for example analkali metal hydroxide, such as sodium or potassium hydroxide, or, inparticular, using a metal alcoholate of the respective hydroxy compoundor its preparation in situ in the presence of a strong base, for exampleof an alkali metal hydride, such as sodium hydride, or in the presenceof an alkali metal, such as sodium, in the absence or presence ofsuitable solvents or solvent mixtures, in particular aprotic solvents,for example of DMPU, an ether, such as diethyl ether, dioxane ortetrahydrofuran, of a carboxamide, such as dimethylformamide, or of amixture of two or more of these solvents, at temperatures of between 0°C. and reflux temperature, in particular between 20° C. and refluxtemperature, if necessary under protective gas, such as nitrogen orargon.

Depending on the reaction conditions, the substitution can proceed as anucleophilic substitution of the first or second order.

Since a series of side reactions (for example racemization by theformation of carbanions etc.) are possible in the reaction according toprocess e), this process can sometimes only be carried out under veryprecisely controlled reaction conditions (for example carefulmetering-in of the base which is employed or of the respectivealcoholate, etc.). Possible interfering reactions and suitable reactionconditions are immediately apparent to the person skilled in the art. Ina preferred variant of the process according to the invention forpreparing compounds of the formula I, process e) is excluded for thisreason.

The release of functional groups which are protected by protectivegroups in the resulting compounds of the formula I having protectedfunctions is effected using one or more of the methods specified underprocess f).

Process f) (protective group detachment)

Detachment of the protective groups which are not components of thedesired end product of the formula I, for example the carboxyl, amino,hydroxyl and/or mercapto protective groups, is effected in a mannerknown per se, for example using solvolysis, in particular hydrolysis,alcoholysis or acidolysis, or by means of reduction, in particularhydrogenolysis, or by means of other reducing agents, and alsophotolysis, as desired stepwise or simultaneously, with it also beingpossible to use enzymic methods. Detachment of the protective groups isdescribed, for example, in the standard works which are mentioned abovein the section on "protective groups".

Thus, a protected carboxyl, for example, for examplelower-alkoxycarbonyl (which is preferably branched in the 1 position),such as tert-lower-alkoxycarbonyl, lower-alkoxycarbonyl which issubstituted in the 2 position by a tri-substituted silyl group or in the1 position by lower alkoxy or lower-alkylthio, ordiphenylmethoxycarbonyl which is unsubstituted or substituted, can beconverted into free carboxyl by treatment with a suitable acid, such asformic acid, acetic acid, hydrochloric acid or trifluoroacetic acid, ifdesired while adding a nucleophilic compound, such as phenol or anisole.Benzyloxycarbonyl which is unsubstituted or substituted can, forexample, be set free by means of hydrogenolysis, i.e. by treatment withhydrogen in the presence of a metallic hydrogenation catalyst, such as apalladium catalyst. In addition, suitably substituted benzyloxycarbonyl,such as 4-nitrobenzyloxycarbonyl, can also be converted into freecarboxyl by reduction, for example by treatment with an alkali metaldithionite, such as sodium dithionite, or with a reducing metal, forexample zinc, or a reducing metal salt, such as a chromium(II) salt, forexample chromium(II) chloride customarily in the presence of ahydrogen-releasing agent which, together with metal, can produce nascenthydrogen, such as an acid, primarily a suitable carboxylic acid, such asa lower-alkanecarboxylic acid which is unsubstituted or substituted, forexample, by hydroxyl, for example acetic acid, formic acid, glycolicacid, diphenylglycolic acid, lactic acid, mandelic acid,4-chloromandelic acid or tartaric acid, or an alcohol or thiol, withwater preferably being added. By means of treating with a reducing metalor metal salt, as described above, 2-halo-lower-alkoxycarbonyl (ifdesired after converting a 2-bromo-lower-alkoxycarbonyl group into acorresponding 2-iodo-lower-alkoxycarbonyl group) or aroylmethoxycarbonylcan also be converted into free carboxyl. Aroylmethoxycarbonyl can becleaved by treating with a nucleophilic, preferably salt-formingreagent, such as sodium thiophenoxide or sodium iodide. The carboxylgroup can also be set free from 1-aryl-lower-alkoxycarbonyl, for examplearylmethoxycarbonyl, such as benzyloxycarbonyl, by hydrolysing in thepresence of a base such as an alkali metal hydroxide, for example sodiumor potassium hydroxide. 2-(Tri-substituted silyl)-lower-alkoxycarbonyl,such as 2-tri-lower-alkylsilyl-lower-alkoxycarbonyl, can also beconverted into free carboxyl by treating with a salt of hydrofluoricacid which provides the fluoride anion, such as an alkali metalfluoride, for example sodium or potassium fluoride, in the absence orpresence of a macrocyclic polyether ("crown ether"), or with a fluorideof an organic quaternary base, such as tetra-lower-alkylammoniumfluoride or tri-lower-alkylaryl-lower-alkylammonium fluoride, forexample tetraethylammonium fluoride or tetrabutylammonium fluoride, inthe presence of an aprotic, polar solvent, such as dimethyl sulfoxide,N,N-dimethylformamide or N,N-dimethylacetamide. Carboxyl which isprotected as organic silyloxycarbonyl, such astri-lower-alkylsilyloxycarbonyl, for example trimethylsilyloxycarbonyl,can be released solvolytically in a customary manner, for example bytreating with water, an alcohol or acid, or, in addition, fluoride, asdescribed above. Esterified carboxyl can also be set free enzymically,for example using esterases or suitable peptidases, for exampleesterified arginine or lysine, such as lysine methyl ester, usingtrypsin. Carboxyl which is protected as an internal ester, such as aγ-lactone, can be released by hydrolysis in the presence of ahydroxide-containing base, such as an alkaline earth metal hydroxide or,in particular, an alkali metal hydroxide, for example NaOH, KOH or LiOH,in particular LiOH, with the corresponding protected hydroxyl groupbeing set free simultaneously.

A protected amino group is set free in a manner which is known per seand which differs depending on the nature of the protective groups,preferably using solvolysis or reduction. Lower-alkoxycarbonylamino,such as tert-butoxycarbonylamino, can be cleaved in the presence ofacids, for example mineral acids, for example hydrohalic acid, such ashydrochloric acid or hydrobromic acid, in particular hydrobromic acid,or of sulfuric acid or phosphoric acid, preferably of hydrochloric acid,or of relatively strong organic acids, such as formic acid,trichloroacetic acid or trifluoroacetic acid, in polar solvents, forexample water or a carboxylic acid, such as acetic acid or formic acid,halohydrocarbons, such as chlorinated lower-alkanes, for exampledichloromethane or chloroform, or ethers, preferably cyclic ethers, suchas dioxane, or in organic carboxylic acids which are liquid at thereaction temperature, without solvent, for example in formic acid.2-Halo-lower-alkoxycarbonylamino (if desired, after converting a2-bromo-lower-alkoxycarbonylamino group into a2-iodo-lower-alkoxycarbonylamino group), aroylmethoxycarbonylamino or4-nitrobenzyloxycarbonylamino can, for example, be cleaved by treatingwith a suitable reducing agent, such as zinc in the presence of asuitable carboxylic acid, such as aqueous acetic acid.Aroylmethoxycarbonylamino can also be cleaved by treating with anucleophilic, preferably salt-forming, reagent such as sodiumthiophenoxide, and 4-nitrobenzyloxycarbonylamino also by treating withan alkali metal dithionite, for example sodium dithionite. Substitutedor unsubstituted diphenylmethoxycarbonylamino,tert-lower-alkoxycarbonylamino or 2-(trisubstitutedsilyl)-lower-alkoxycarbonylamino, such as2-tri-lower-alkylsilyl-lower-alkoxycarbonylamino, can be cleaved bytreating with a suitable acid, for example formic or trifluoroaceticacid, for example in a halogenated hydrocarbon, such as methylenechloride or chloroform (in particular, if hydroxyl which issimultaneously protected with benzyl is not to be set free),1-aryl-lower-alkoxycarbonylamino, such as substituted or unsubstitutedbenzyloxycarbonylamino, can, for example, be cleaved by means ofhydrogenolysis, i.e. by treating with hydrogen in the presence of asuitable hydrogenation catalyst, such as a palladium catalyst, forexample bound to a support material, such as carbon, preferably in polarsolvents, such as di-lower-alkyl-lower-alkanoylamides, for exampledimethylformamide, ethers, such as cyclic ethers, for example dioxane,esters, such as lower-alkyl lower-alkanoates, for example ethyl acetate,or alcohols, such as methanol, ethanol or propanol, with methanol beingparticularly preferred, preferably, for example, at room temperature,substituted or unsubstituted triarylmethylamino or formylamino can becleaved, for example, by treating with an acid, such as a mineral acid,for example hydrochloric acid, or an organic acid, for example formic,acetic or trifluoroacetic acid, if desired in the presence of water, andtriphenylaminomethyl can be cleaved, in particular, by hydrogenolysisusing a precious metal or precious metal oxide as catalyst, such asplatinum, palladium or, in particular, palladium hydroxide, with thecatalyst preferably being bonded to a support material, such as carbon,silica gel or aluminium oxide, in inert solvents, such as an ester, orpreferably a lower-alkyl lower-alkanoate, such as ethyl acetate, attemperatures of from 20 to 80° C., in particular of from 50 to 70° C.,if required under elevated pressure, for example between about 1 and 10bar, and an amino group which is protected as silylamino can be setfree, for example, by means of hydrolysis or alcoholysis. An amino groupwhich is protected by 2-haloacetyl, for example 2-chloroacetyl, can beset free by treating with thiourea in the presence of a base, or with athiolate salt, such as an alkali metal thiolate of the thiourea, andsubsequent solvolysis, such as alcoholysis or hydrolysis, of theresulting substitution product. An amino group which is protected by2-(trisubstituted silyl)-lower-alkoxycarbonyl, such as2-tri-lower-alkylsilyl-lower-alkoxycarbonyl, can also be converted intothe free amino group by treating with a fluoride anion-providing salt ofthe hydrofluoric acid, as indicated above in connection with the releaseof a correspondingly protected carboxyl group. Silyl, such astrimethylsilyl or tert-butyldimethylsilyl, which is bonded directly to aheteroatom, such as nitrogen, can likewise be detached with fluorideions, preferably using a fluoride of an organic, quaternary nitrogenbase, such as tetra-lower-alkylammonium fluoride ortri-lower-alkylaryl-lower-alkylammonium fluoride, for exampletetraethylammonium fluoride or tetrabutylammonium fluoride, in thepresence of an aprotic, polar solvent, such as dimethyl sulfoxide orN,N-dimethylacetamide, or, in particular, of an ether, such astetrahydrofuran, at temperatures between 0 and 50° C., in particular,for example, at room temperature.

Amino which is protected in the form of an azido group is converted intofree amino, for example, by means of reduction for example by means ofcatalytic hydrogenation with hydrogen in the presence of a hydrogenationcatalyst, such as platinum oxide, palladium or Raney nickel, by means ofreduction with mercapto compounds, such as dithiothreitol ormercaptoethanol, or by treating with zinc in the presence of an acid,such as acetic acid. The catalytic hydrogenation is preferably carriedout in an inert solvent, such as a halogenated hydrocarbon, for examplemethylene chloride, or else in water or a mixture of water and anorganic solvent, such as an alcohol or dioxane, at from approximately20° C. to 25° C., or else while cooling or heating.

A hydroxyl group or mercapto group which is protected by a suitable acylgroup, a tri-lower-alkylsilyl group or by substituted or unsubstituted1-aryl(such as l-phenyl)-lower-alkyl is set free in an analogous mannerto a correspondingly protected amino group. A hydroxyl group or mercaptogroup which is protected by 2,2-dichloroacetyl is set free, for example,by basic hydrolysis, while a hydroxyl group or mercapto group which isprotected by tert-lower-alkyl or by a 2-oxa- or 2-thia-aliphatic or-cycloaliphatic hydrocarbon radical is set free by acidolysis, forexample by treating with a mineral acid or a strong carboxylic acid, forexample trifluoroacetic acid. A hydroxyl group which is protected bybenzyloxy is set free, for example, by means of hydrogenolysis, i.e. bytreating with hydrogen in the presence of a suitable hydrogenationcatalyst, such as a palladium catalyst, for example bound to a supportmaterial, such as charcoal, preferably in polar solvents, such asdi-lower-alkyl-lower-alkanoylamides, for example dimethylformamide,ethers, such as cyclic ethers, for example dioxane, esters, such aslower-alkylalkanoates, for example ethyl acetate, chlorinatedhydrocarbons, such as dichloromethane, or alcohols, such as methanol,ethanol or propanol, with methanol being particularly preferred, ormixtures of two or more of these solvents, preferably, for example, atroom temperature. Mercapto which is protected by pyridyldiphenylmethylcan, for example, be set free by mercury(II) salts at pH 2-6 or byzinc/acetic acid or electrolytic reduction, acetamidomethyl andiso-butyrylamidomethyl, for example, by reaction with mercury(II) saltsat pH 2-6, 2-chloroacetamidomethyl, for example, by1-piperidinothiocarboxamide, S-ethylthio, S-tert-butylthio and S-sulfo,for example, by means of thiolysis with thiophenol, thioglycolic acid,sodium thiophenoxide or 1,4-dithiothreitol. Two hydroxyl groups, or anadjacent amino group and hydroxyl group, which are together protected bymeans of a bivalent protective group, preferably, for example, amethylene group which is substituted once or twice by lower alkyl, suchas by lower alkylidene, for example isopropylidene, cycloalkylidene, forexample cyclohexylidene, or benzylidene, can be set free by acidicsolvolysis, particularly in the presence of a mineral acid or a strongorganic acid. A tri-lower-alkylsilyl group is likewise detached by meansof acidolysis, for example by mineral acid, preferably hydrofluoricacid, or a strong carboxylic acid. Hydroxyl can also preferably be setfree from tri-lower-alkylsilyloxy by treating with a fluorideanion-providing salt of hydrofluoric acid, such as an alkali metalfluoride, for example sodium or potassium fluoride, in the absence orpresence of a macrocyclic polyether ("crown ether"), or with a fluorideof an organic quaternary base, such as tetra-lower-alkylammoniumfluoride or tri-lower-alkylaryl-lower-alkylammonium fluoride, forexample tetraethylammonium fluoride or tetrabutylammonium fluoride, inthe presence of an aprotic, polar solvent, such as dimethyl sulfoxide orN,N-dimethylacetamide. 2-Halo-lower-alkoxycarbonyl is removed by theabovementioned reducing agents, for example reducing metal, such aszinc, reducing metal salts, such as chromium (II) salts, or by sulfurcompounds, for example sodium dithionite or, preferably, sodium sulfideand carbon disulfide. Esterified hydroxyl groups, for examplelower-alkanoyloxy, such as acetyloxy, can also be set free withesterases, while acylated amino can, for example, be set free usingsuitable peptidases.

The temperatures for the release of the protected functional groups arepreferably between -80° C. and the boiling temperature of the reactionmixture, in particular between -80 and 110° C.; particularly preferablybetween -20 and 50° C., for example between 10 and 35° C., such as, forexample, at room temperature, or at from 80° C. up to the boilingtemperature of the reaction mixture concerned, for example atapproximately 100° C.

When several protected functional groups are present, the protectivegroups are, if desired, selected such that more than one such group canbe detached simultaneously, for example acidolytically, as by means oftreating with trifluoroacetic acid, or with hydrogen and a hydrogenationcatalyst, such as a palladium charcoal catalyst. Conversely, the groupscan also be selected such that they cannot all be detachedsimultaneously but, instead, in a desired sequence, with thecorresponding intermediates being obtained.

Additional process measures

In the additional process measures, which are carried out if desired,functional groups of the starting compounds which are not to participatein the reaction can be unprotected or in protected form, for exampleprotected by one or more of the protective groups specified underprocess a). The protective groups can be detached, in their entirety orin part, using one of the methods specified under process f).

Salts of compounds of the formula I having at least one salt-forminggroup can be prepared in a manner known per se. Thus, salts of compoundsof the formula I having acidic groups can be formed, for example, bytreating with metal compounds, such as alkali metal salts of suitableorganic carboxylic acids, for example the sodium salt of 2-ethylhexanoicacid, with inorganic alkali metal or alkaline earth metal compounds,such as the corresponding hydroxides, carbonates or hydrogen carbonates,such as sodium and potassium hydroxide, carbonate or hydrogen carbonate,with corresponding calcium compounds or with ammonia, or with a suitableorganic amine, with stoichiometric quantities, or only a small excess ofthe salt-forming agent, preferably being used. Acid addition salts ofcompounds of the formula I are obtained in a customary manner, forexample by treating with an acid or a suitable anion exchange reagent.Internal salts of compounds of the formula I which contain acidic andbasic salt-forming groups, for example a free carboxylic group and afree amino group, can be formed, for example, by neutralizing salts,such as acid addition salts, to the isoelectric point, for example usingweak bases, or by treating with ion exchangers.

Salts can be converted into the free compounds in a customary manner,metal salts and ammonium salts can be converted, for example, bytreating with suitable acids or acidic ion exchangers, and acid additionsalts can be converted, for example, by treating with a suitable basicagent, in particular with inorganic alkali metal or alkaline earth metalcompounds, such as the corresponding hydroxides, carbonates orhydrogen-carbonates, such as sodium and potassium hydroxide, carbonateor hydrogen-carbonate, with corresponding calcium compounds or withammonia or a suitable organic amine, with stoichiometric quantities oronly a small excess of the salt-forming agent preferably being used, insuitable solvents, for example halohydrocarbons, such asdichloromethane, in the presence or absence of water; or by means oftreating with basic ion exchangers.

Stereoisomeric mixtures of compounds of the formula I, that is mixturesof diastereomers and/or enantiomers, for example racemic mixtures, canbe resolved into the corresponding isomers in a manner known per seusing suitable separation methods. Thus, diastereomeric mixtures, forexample, can be resolved into the individual diastereomers by fractionalcrystallization, chromatography, solvent partition or other suitablemethods. Racemates can be separated from each other after converting theoptical antipodes into diastereomers, for example by reacting withoptically active compounds, for example optically active acids or bases,by chromatography on column materials coated with optically activecompounds, or by enzymic methods, for example by the selective reactionof only one of the two enantiomers. This separation can be effectedeither at the level of one of the starting products or at that of thecompounds of the formula I.

In a compound of the formula I, in which one of the radicals R₁, R₂ orR₃, or several of these radicals, are substituted by1-phenyl-lower-alkoxy, such as benzyloxy, the 1-phenyl-lower-alkoxyradical can be detached as described under process f). The correspondingcompounds of the formula I are obtained in which hydroxyl is present inplace of 1-phenyl-lower-alkoxy.

In an obtainable compound of the formula I, a carboxyl group which ispresent in free form or in reactive form can be esterified, or anesterified carboxyl group can be converted into a free carboxyl group.

In order to esterify a carboxyl group in a compound of the formula I,the free acid, if desired, can be used, or the free acid can beconverted into one of the reactive derivatives specified above underprocess a) and can be reacted with a corresponding alcohol, or, for theesterification, the free acid or a reactive salt, for example thecaesium salt, can be reacted with a reactive derivative of an alcohol.For example, the caesium salt of a carboxylic acid can be reacted with ahalide or organic sulfonic acid ester corresponding to the alcohol (withhalogen or the radical of an organic sulfonic acid, such astoluenesulfonic acid, in place of the hydroxyl group). Theesterification of the carboxyl group can also be effected using othercustomary alkylating agents, for example using diazomethane, lower-alkylhalides, sulfonic acid esters, Meerwein salts or 1-substituted3-aryltriazenes.

In order to convert an esterified carboxyl group into the free carboxylgroup, use can be made of one of the methods described above inassociation with the detachment of the carboxyl protective groups or, ifdesired, of an alkaline hydrolysis under customary conditions, such asthose specified under process f), preferably in the presence of analkali metal hydroxide, such as LiOH, in suitable solvents, such asalcohols, for example methanol or ethanol, water or mixtures thereof.

A lower-alkoxycarbonyl-lower-alkoxy group which is present as asubstituent, for example of phenyl or naphthyl R₂ and/or R₃, can beconverted reductively into a hydroxy-lower-alkoxy group (in which thelower alkyl radical has at least 2 carbon atoms) by, for example,reducing with complex hydrides which selectively reduce the carbonylester group under suitable reaction conditions, for example using LiBH₄in 1,2-dimethoxyethane at temperatures of from 0° C. up to the refluxtemperature, preferably from about 15 to 30° C.

In a compound of the formula I, a free amino or imino group which ispresent can be acylated, for example, for introducing alower-alkoxycarbonyl radical on the nitrogen of piperidinylcarbonyl R₁.The acylation is effected in analogy with the methods specified aboveunder process a) or in analogy with one of the methods specified forprotective groups.

In an obtainable compound of the formula I, in which the substituentshave the said meanings and there is at least one free hydroxyl group,and additional functional groups are, if necessary, present in protectedform, the free hydroxyl group, for example the hydroxyl group on thephenyl or naphthyl R₂ and/or phenyl or naphthyl R₃, can be etherified,which hydroxyl group can be etherified with the radical of alower-alkanol, of a phenyl-lower-alkanol, of alower-alkoxy-carbonyl-lower-alkanol, of a carbamoyl-lower-alkanol, of apyridyl-lower-alkanol, of a cyano-lower-alkanol or of alower-alkoxy-lower-alkanol, with the said alcohols preferably beingemployed in a form in which a nucleofugic leaving group is present inplace of the hydroxyl group, for example as defined for W₁ in compoundsof the formula X.

The etherification can be carried out in analogy with the processconditions according to process e) and is preferably effected usingdiazomethane or lower-alkyl-, phenyl-lower-alkyl-,lower-alkoxy-lower-alkyl-, carbamoyl-lower-alkyl-, pyridyl-lower-alkyl-,cyano-lower-alkyl- or lower-alkoxy-lower-alkyl-halides or -sulfonic acidesters. The reaction is preferably carried out using appropriatelower-alkyl-, phenyl-lower-alkyl-, lower-alkoxy-lower-alkyl-,carbamoyl-lower-alkyl-, pyridyl-lower-alkyl-, cyano-lower-alkyl- orlower-alkoxy-lower-alkyl-halides, such as -iodides, -bromides or-chlorides, in the presence of bases, preferably of a hydroxyl base, inparticular a basic metal hyroxide, such as sodium or potassiumhydroxide, or, especially, of a metal carbonate or metal hydrogencarbonate, such as sodium, potassium or, primarily, caesium carbonate insuitable solvents or solvent mixtures, for example inN,N-di-lower-alkyl-lower-alkanoylamides, such as dimethylformamide ordimethylacetamide, ketones, such as lower-alkanones, for exampleacetone, or ethers, such as dioxane, or mixtures thereof, attemperatures of between -10° C. up to the reflux temperature, preferablyat from 0 to 60° C., for example at from about 0 to 50° C.

In a compound of the formula I, groups which are present and whichcorrespond to protective groups, or, in addition, suitable RI radicals,apart from hydrogen, can be detached using one of the methods specifiedunder process f), in particular by hydrolysis, for example in thepresence of bases, such as alkali metal or alkaline earth metalhydroxides, for example sodium hydroxide, or acids, such as organicacids or mineral acids, for example hydrohalic acid, such ashydrochloric acid. The hydrolysis is effected under the customaryconditions, for example in aqueous solution or in anhydrous solvents, inparticular in ethers, such as dioxane, at temperatures of between -50°C. and the reflux temperature of the corresponding reaction mixtures,for example between 0° C. and 50° C., preferably in the presence of aprotective gas, such as argon or nitrogen, or by means of hydrogenolysis(for example in the case of benzyloxycarbonyl radicals), preferably inpolar solvents, such as alcohols, for example methanol or ethanol, or ofesters, such as lower-alkyl-lower-alkanoates, for example ethyl acetate,at the abovementioned temperatures and in the presence of suitablehydrogenation catalysts, such as a palladium catalyst, which ispreferably bound to a support, such as charcoal.

In a compound of the formula I, in which at least one of the radicals R₂or R₃ is a phenyl group and/or one or more additional phenyl rings arepresent, with it also being possible for the phenyl radicals to be ineach case substituted, as described above, the corresponding phenylradical(s) can be hydrogenated selectively to form correspondingcyclohexyl radicals. The hydrogenation is preferably effected in thepresence of a catalyst which permits selective hydrogenation of doublebonds in the presence of amide bonds, in particular of a catalystcomposed of heavy metal oxides such as an Rh(III)/Pt(VI) oxide catalystin accordance with Nishimura (S. Nishimura, Bull. Chem. Soc. Japan 33,566 (1960), in suitable solvents, in particular water, alcohols, such asmethanol or ethanol, esters, such as ethyl acetate, or ethers, such asdioxane, for example in methanol, at temperatures of from 0 to 150° C.,preferably of from 10 to 50° C., for example at room temperature; athydrogen pressures of from 0.01 to 50 bar, for example under standardpressure or low pressure.

In a compound of the formula I, in which at least one of the radicals R₂or R₃ is cyclohexenyl, the corresponding cyclohexenyl radical can beselectively hydrogenated to give the corresponding cyclohexyl radical,in suitable solvents or solvent mixtures, preferably dissolved in analcohol, such as methanol or ethanol, an ester, for example lower-alkyllower-alkanoate, such as ethyl acetate, or a mixture of these solvents,in the presence of a catalyst, for example palladium which is preferablybound to a support, such as charcoal, preferably active charcoal, atpreferred temperatures of between 10 and 50° C., preferably at roomtemperature, under slightly elevated or reduced pressure or, preferably,standard pressure.

In a compound of the formula I, in which nitro groups are bonded toaromatic radicals (aryl), in particular if R₁ is arylsulfonyl having oneor more nitro substituents, such as 4-nitrobenzenesulfonyl, nitro can bereduced to amino by, in particular, hydrogenating in suitable solventsor solvent mixtures, preferably dissolved in an alcohol, such asmethanol or ethanol, an ester, for example lower-alkyl lower-alkanoate,such as ethyl acetate, or a mixture of these solvents, in the presenceof a catalyst, for example of a skeleton catalyst, such as Raney nickel,at preferred temperatures of between 10 and 50° C., in particular roomtemperature, under slightly increased or reduced pressure or,preferably, standard pressure.

Pharmaceutical preparations and methods

The invention also relates to pharmaceutical preparations which comprisecompounds of the formula I, in particular of the formula I'. Thepharmacologically utilizable compounds of the present invention can beused, for example, for producing pharmaceutical preparations whichcomprise an effective quantity of the active compound together, or in amixture, with a significant quantity of inorganic or organic, solid orliquid, pharmaceutically utilizable carrier substances.

The pharmaceutical preparations according to the invention are those forenteral, such as nasal, buccal, rectal or oral, or parenteral, such asintramuscular or intravenous, administration to mammals (humans andanimals) and comprise an effective dose of the pharmacological activecompound on its own or together with a significant quantity of apharmaceutically utilizable carrier material.

The dose of the active compound depends on the mammalian species, thebody weight, the age and the individual condition, the individualpharmacokinetic circumstances, the disease to be treated and the mode ofadministration.

The invention also relates to pharmaceutical preparations and to amethod for treating diseases caused by retroviruses, for example AIDS orits preliminary stages, in particular when HIV-2 or, especially, HIV-1causes the disease, or, in addition, for treating analogous diseases, ortheir preliminary stages, in non-human mammals which are caused, forexample, by SIV in monkeys or FIV in cats, preferably wherein aquantity, which is therapeutically effective against retroviraldiseases, such as AIDS or its preliminary stages, or analogous diseasesin non-human mammals, of a novel compound of the formula I or, inparticular, I' is included in a pharmaceutical preparation which issuitable for administration to a mammal, in particular humans, fortreating a retroviral disease, such as, preferably, AIDS or, inaddition, analogous diseases in non-human mammals, or wherein atherapeutically effective quantity of a novel compound of the formula Ior, in particular I' is administered, in association with the treatmentmethod, to a mammal, for example humans, which, on account of one of thesaid diseases, in particular AIDS or its preliminary stages, or, inaddition, corresponding diseases in non-human mammals, requires atreatment of this nature, in a quantity which is therapeuticallyeffective against retroviral diseases, such as AIDS or its preliminarystages, or, in addition, corresponding diseases in non-human mammals.The dose quantities to be administered to mammals, for example humans ofabout 70 kg body weight, are between about 3 mg and about 10 g,preferably between about 20 mg and about 4 g, for example approximately100 mg to 2.5 g per person and day, distributed, preferably, between 1to 3 individual doses which can, for example, be of equal size.Customarily, children are given half the dose given to adults."Therapeutically effective" means, in particular, that the onset of theparticular disease can be retarded when compared with the untreatedpatient, that at least one symptom can be delayed or attenuated, that atleast one cell type (for example human CD4 cells) can be fully orpartially protected from the disease, or that the disease can even becompletely cured.

The pharmaceutical preparations comprise from about 1% to about 95%,preferably from about 20% to about 90%, of the active compound.Pharmaceutical preparations according to the invention can, for example,be present in unit dose form, such as ampoules, vials, suppositories,coated tablets, tablets or capsules.

The pharmaceutical preparations of the present invention are produced ina manner known per se, for example using conventional solubilizing,lyophilizing, mixing, granulating or coating methods.

Use is preferably made of solutions of the active compound, and inaddition also suspensions or dispersions, specifically, and inparticular, isotonic aqueous solutions, dispersions or suspensions, withit being possible for these, for example in the case of lyophilizedpreparations, which comprise the active substance alone or together witha carrier material, for example mannitol, to be prepared prior to use.The pharmaceutical preparations can be sterilized and/or compriseauxiliary substances, for example preservatives, stabilizers,crosslinking agents and/or emulsifiers, solubilizers, salts forregulating the osmotic pressure and/or buffers, and are produced in amanner known per se, for example using conventional solubilizing orlyophilizing methods. The said solutions or suspensions can compriseviscosity-increasing substances, such as sodium carboxymethylcellulose,carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.

Suspensions in oil contain, as the oily component, the vegetable,synthetic or semi-synthetic oils which are customary for injectionpurposes. Oils of this nature which are to be mentioned are, inparticular, liquid fatty acid esters which, as acid component, contain along-chain fatty acid having 8-22, in particular 12-22, carbon atoms,for example lauric acid, tridecanoic acid, myristic acid, pentadecanoicacid, palmitic acid, margaric acid, stearic acid, arachidonic acid,behenic acid, or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brassidic acid or linoeic acid, with orwithout the addition of antioxidants, for example vitamin E, β-caroteneor 3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of thesefatty acid esters has at most 6 carbon atoms and is a mono- orpoly-hydric, for example monohydric, dihydric or trihydric alcohol, forexample methanol, ethanol, propanol, butanol or pentanol, or theirisomers, especially, however, glycol and glycerol. Fatty acids whichare, therefore, to be mentioned by way of example are: ethyl oleate,isopropyl myristate, isopropyl pamitate, "Labrafil M 2375"(polyoxyethyleneglycerol trioleate from Gattefosse, Paris), "Miglyol812" (triglyceride of saturated fatty acids of C₈ to C₁₂ chain lengthfrom Huils AG, Germany), particularly, however, vegetable oils such ascottonseed oil, almond oil, olive oil, castor oil, sesame oil, soya beanoil and, especially, groundnut oil.

The production of the injection preparations is effected in a customarymanner under sterile conditions, as is their filling into ampoules orvials, and the sealing of the containers.

Pharmaceutical preparations for oral use can be obtained by combiningthe active compound with solid carrier substances, if desiredgranulating a mixture which is obtained and, if desired or necessary,after having added suitable auxiliary substances, processing intotablets, coated tablet cores or capsules, or else by preparingdispersions, preferably with phospholipids, which are filled into glassvials. At the same time, the active compounds can also be incorporatedinto synthetic supports which release them in a metered manner or elseallow them to diffuse.

Suitable carrier substances are, in particular, fillers, such as sugars,for example lactose, sucrose, mannitol or sorbitol, cellulosepreparations, and/or calcium phosphates, for example tricalciumphosphate or calcium hydrogen phosphate and, in addition, binders, suchas starch pastes using, for example, corn starch, wheat starch, ricestarch or potato starch, gelatin, tragacanth, methylcellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone, and/or, if desired, disintegrants, such as theabovementioned starches, and, in addition, carboxymethyl starch,crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof,such as sodium alginate. Adjuvants are primarily flow regulators andlubricants, for example silicic acid, talc, stearic acid or saltsthereof, such as magnesium or calcium stearate, and/or polyethyleneglycol. Coated tablet cores are provided with suitable coatings whichare or are not resistant to gastric juices, with, inter alia,concentrated sugar solutions, which do or do not contain gum arabic,talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide,lacquer solutions in suitable organic solvents or, for preparing gastricjuice-resistant coatings, solutions of suitable cellulose preparations,such as ethylcellulose phthalate or hydroxypropylmethylcellulosephthalate, being used.

Capsules are hard gelatin capsules and also soft, closed capsules madeof gelatin and an emollient, such as glycerol or sorbitol. The hardcapsules can contain the active compound in the form of a granulate, forexample containing fillers, such as lactose, binders, such as starches,and/or glidants, such as talc or magnesium stearate, and, if desired,containing stabilizers. In capsules, the active compound is preferablysuspended or dissolved in suitable, oily auxiliary substances, such ascustomary vegetable, synthetic or semi-synthetic oils. Oils of thisnature which are to be mentioned, in particular are liquid fatty esterswhich contain, as the acid component, a long-chain fatty acid, forexample having 8-22, in particular 12-22, carbon atoms, for examplelauric acid, tridecanoic acid, myristic acid, pentadecanoic acid,palmitic acid, margaric acid, stearic acid, arachidonic acid, behenicacid, or corresponding unsaturated acids, for example oleic acid,elaidic acid, erucic acid, brassidic acid or linoleic acid, with orwithout the addition of antioxidants, for example, vitamin E, β-caroteneor 3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of thesefatty acid esters has at most 6 carbon atoms and is a mono- orpoly-hydric, for example monohydric, dihydric or trihydric alcohol, forexample methanol, ethanol, propanol, butanol or pentanol or theirisomers, especially, however, ethylene glycol or propylene glycol andglycerol. Fatty acid esters which are to be mentioned therefore, by wayof example, are: ethyl oleate, isopropyl myristate, isopropyl palmitate,"Labrafil M 2375" (polyoxyethyleneglycerol trioleate from Gattefosse,Paris), "Miglyol 812" (triglyceride of saturated fatty acids of C₈ toC₁₂ chain length from Huls AG, Germany), particularly, however,vegetable oils, such as cottonseed oil, almond oil, olive oil, castoroil, groundnut oil, soya bean oil and, especially, sesame oil. Paraffinoil is also possible. Stabilizers, such as emulsifiers, wetting agentsor surfactants, binders, such as starch pastes using, for example, cornstarch, wheat starch, rice starch or potato starch, gelatin, tragacanth,methylcellulose, hydroxypropylmethylcellulose (preferably), sodiumcarboxymethylcellulose, cyclodextrin(s) and/or polyvinylpyrrolidone,and/or anti-bacterial agents, can be added. Suitable emulsifiers are, inparticular, oleic acid, non-ionic surfactants of the fatty acidpolyhydroxyalcohol ester type, such as sorbitan monolaurate, -oleate,-stearate or -palmitate, sorbitan tristearate or -trioleate,polyoxyethylene adducts of fatty acid polyhydroxyalcohol esters, such aspolyoxyethylenesorbitan monolaurate, -oleate, -stearate, -palmitate,-tristearate or -trioleate, polyethylene glycol fatty acid esters, suchas polyoxyethyl stearate, polyoxyethylene glycol-(300 or 400)-stearate,polyethylene glycol-2000-stearate, in particular ethyleneoxide-propylene oxide block polymers of the ®Pluronic (Wyandotte Chem.Corp.; trademark of BASF, FRG) or ®Synperonic (ICI) type. If it is notsoluble in the said oils, the active substance is preferably present insuspension form, for example with the active substance having a particlesize of between about 1 and 100 μm.

Dyes or pigments can be added to the tablets or coated tablet coatingsand to the capsule shells, for example for identifying or for labellingdifferent doses of active compound.

The compounds of the formula I can be present either alone or incombination with other compounds which are effective againstretroviruses, and used as mentioned above.

The invention also relates, correspondingly, to a process or a methodfor treating diseases caused by retroviruses, for example AIDS or itspreliminary stages, in particular when HIV-2 or, especially, HIV-1 iscausing the disease, or, in addition, analogous diseases, or theirpreliminary stages, in non-human mammals, for example those caused bySIV in monkeys or FIV in cats, which comprises administering acombination, which is therapeutically effective against retroviraldiseases, such as AIDS or its preliminary stages, or analogous diseasesin non-human mammals, of a) a novel compound of the formula I or, inparticular, I' (or else several of these compounds) and b) anothercompound, or two or more thereof, which is/are effective againstretroviruses, in particular several or, preferably, one of theinhibitors, mentioned above as being preferred, of reverse transcriptaseor, in particular, retroviral aspartate proteases (which, for example,is included in a pharmaceutical product or preparation which is suitablefor administering to a mammal, in particular humans, which are in needof such treatment, for treating a retroviral disease, such as,preferably, AIDS or else analogous diseases in non-human mammals) in aquantity which is therapeutically effective against retroviral diseases,such as AIDS or its preliminary stages, or else corresponding diseasesin non-human mammals. The dose quantities of the combined individualactive compounds which are to be administered to mammals, for examplehumans, of about 70 kg body weight are between about 3 mg and about 10g, preferably between about 20 mg and about 4 g, for example fromapproximately 50 mg to 2.5 g per person and day, preferably dividedbetween 1 to 3 individual doses which can, for example, be of equalsize. Customarily, children are given half the dose given to adults."Therapeutically effective" means, in particular, that the onset of therespective disease can be retarded as compared with the untreatedpatient, that at least one symptom can be delayed or attenuated, that atleast one cell type (for example human CD4 cells) can be fully orpartially protected from the disease, or that the disease can even becompletely cured.

The invention also relates to products which comprise a) at least, andpreferably, one compound of the formula I, or a salt thereof, providinga salt-forming group is present, and b) one, two (preferred) or moreother active compounds which are effective against retroviruses, inparticular HIV, such as HIV-1 or HIV-2, selected, in particular, fromthe abovementioned inhibitors of reverse transcriptase or, especially,from the abovementioned other inhibitors of retroviral aspartateproteases (in particular the inhibitors described above in each case asbeing preferred), in the presence or absence of one or morepharmaceutically acceptable carrier materials, as combinationpreparations for simultaneous or chronologically staggered use within atime span which is small enough for the active compounds both of thecomponent a) and of the component b) to be present simultaneously in thepatient (for example in blood), for treating a retroviral disease whichresponds to active compounds of this type. The underlying concept isthat synergisms can occur in this way.

The invention also relates to pharmaceutical preparations which comprisea (preferably jointly) antiretrovirally active quantity of a) at least(and preferably) one compound of the formula I and b) one or more of thesaid active compounds which are effective against retroviruses, with orwithout one or more pharmaceutically acceptable carrier material(s),with the active compounds described above in each case as beingpreferred being preferred.

The invention furthermore relates to the use of a combination of a) acompound of the formula I and b) one or more of the abovementionedactive compounds which are effective against retroviruses (in particularHIV, such as HIV-1 or HIV-2) for producing pharmaceutical preparationsto be used as compositions against retroviral infections, in particularcaused by HIV, such as HIV-1 or HIV-2; with the compounds mentioned ineach case as being preferred being preferred.

The invention also relates to the provision of the abovementionedproduct or compound mixture for use in a process for the therapeutictreatment of the human or animal body.

In this context, the composition and production of the pharmaceuticalpreparations for the individual components of a product for staggered orsimultaneous administration, or for the compound mixtures, are analogousto those of the abovementioned pharmaceutical preparations for activecompounds of the formula I.

In each case, a combination of a) the compound of the formula I havingthe designation 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!-hexanoyl-(L)-Val-N-(2-methoxyethyl)amideand b) one or two of the active compounds saquinavir or indinavir isparticularly preferred.

The active compounds of the formula I and/or the other active compoundswhich are effective against retroviruses can in each case be replaced bytheir pharmaceutically utilizable salts.

Starting materials:

Novel starting materials and/or intermediates, and also methods fortheir preparation, are likewise the subject-matter of the presentinvention. Preferably, those starting compounds are used, and reactionconditions chosen, such that the compounds listed as being preferred areobtained.

All starting materials can preferably be prepared in analogy with themethods specified in the examples or else, for example, as described inEP 0 532 466 (published on 17 March 1993) or EP 0 618 222 (published onOct. 5, 1994); these applications are incorporated into the present textby reference.

In the preparation of all the starting materials, free functional groupswhich are not to participate in the respective reaction can beunprotected or, if necessary, be in protected form, for exampleprotected by the protective groups mentioned above under process a),which groups can be introduced at appropriate stages in analogy with themethods mentioned there. Protective groups, or the protected groups, canbe set free at suitable time points in analogy with the methodsdescribed under process f). Starting materials and intermediates havingsalt-forming groups can in each case be used as free compounds or assalts, and salts can, at every stage, be prepared or converted onceagain into the free compounds.

In analogy with the process steps described above for the additionalprocess measures, hydroxyl-substituted phenyl R₂ and/or phenyl R₃radicals in intermediates can be etherified, at appropriate reactionstages, with the radical of a lower alkanol, a phenyl-lower-alkanol, alower-alkoxy-carbonyl-lower-alkanol, a carbamoyl-lower-alkanol, apyridyl-lower-alkanol, a cyano-lower-alkanol or alower-alkoxy-lower-alkanol. The etherification is preferably effectedusing diazomethane, or lower-alkyl-, phenyl-lower-alkyl-,lower-alkoxycarbonyl-lower-alkyl-, carbamoyl-lower-alkyl,pyridiyl-lower-alkyl-, cyano-lower-alkyl- orlower-alkoxy-lower-alkyl-halides or -sulfonic acid esters. Preference isgiven to the reaction with corresponding lower-alkyl-,phenyl-lower-alkyl-, lower-alkoxycarbonyl-lower-alkyl-,carbamoyl-lower-alkyl-, pyridyl-lower-alkyl-, cyano-lower-alkyl- orlower-alkoxy-lower-alkyl-halides, such as -iodides, -bromides or-chlorides, in the presence of bases, preferably of a hydroxyl base, inparticular a basic metal hydroxide, such as sodium or potassiumhydroxide, or, especially, of a metal carbonate or hydrogen carbonate,such as sodium, potassium or, primarily, caesium carbonate, in suitablesolvents or solvent mixtures, for example inN,N-di-lower-alkyl-lower-alkanoylamides, such as dimethylformamide or-acetamide, ketones, such as lower alkanones, for example acetone, orethers, such as dioxane, or mixtures thereof, at temperatures of from-10° C. up to the reflux temperature, preferably at from 0 to 60° C.,for example from about 0 to 50° C.

In intermediates in which at least one of the radicals R₂ or R₃ is aphenyl group and/or one or more additional phenyl rings are present,with it also being possible for the phenyl radicals in each case to besubstituted, as described above, an appropriate phenyl radical can, atsuitable reaction stages, in analogy with the process steps describedabove for the additional process measures, be selectively reduced, i.e.hydrogenated, to corresponding cyclohexyl radicals. The hydrogenation ispreferably effected in the presence of a catalyst which permits theselective hydrogenation of double bonds in the presence of peptidebonds, in particular of a catalyst consisting of heavy metal oxides,such as a Rh(III)/Pt(VI) oxide catalyst in accordance with Nishimura (S.Nishimura, Bull. Chem. Soc. Japan 33, 566 (1960), in suitable solvents,in particular water, alcohols, such as methanol or ethanol, esters, suchas ethyl acetate, or ethers, such as dioxane, for example in methanol,at temperatures of from 0 to 150° C., preferably of from 10 to 50° C.,for example at room temperature, and under hydrogen pressures of from0.01 to 50 bar, for example under standard pressure or under lowpressure.

In intermediates in which at least one of the radicals R₂ or R₃ iscyclohexenyl, an appropriate cyclohexenyl radical can, at suitablereaction stages, in analogy with the process steps described above forthe additional process measures, be selectively hydrogenated to thecorresponding cyclohexyl radical, for example in suitable solvents orsolvent mixtures, preferably dissolved in an alcohol, such as methanolor ethanol, an ester, for example lower-alkyl lower-alkanolate, such asethyl acetate, or a mixture of these solvents, in the presence of acatalyst, for example palladium which is preferably bound to a support,such as charcoal, preferably active charcoal, at preferred temperaturesof between 10 and 50° C., preferably at room temperature under slightlyelevated or reduced pressure or, in particular, under standard pressure.

Provided the stereochemistry of asymmetric carbon atoms is not defineddirectly by the choice of corresponding bond symbols, the configurationof asymmetric carbon atoms which is in each case preferred is designatedin the formulae by the configuration designation, selected from (S), (R)and (S,R), which is in each case given in brackets. In addition, otherisomers or isomeric mixtures can also be present in place of these.

The carboxylic acids of the formulae II and IV, or reactive derivativesthereof, are known, are commercially available or can be prepared bymethods which are known per se.

The compounds of the formula III and III' are known or can be preparedby methods which are known per se. For example, they can be obtainedfrom compounds of the formula ##STR30## in which R₂ has the meaningsgiven for compounds of the formula I, and Pa is an amino protectivegroup, in particular lower-alkoxycarbonyl, such as tert-butoxycarbonyl,or Of 1-phenyl-lower-alkoxycarbonyl, such as benzyloxycarbonyl (oranalogues thereof in which hydrogen replaces Pa, which analogues canthen be protected subsequently), which are in a first step converted byreduction into the corresponding compounds of the formula ##STR31## (orthe analogue having hydrogen in place of Pa), in which the radicals areas described above.

The reduction of amino acid derivatives of the formula XI to give thecorresponding aldehydes XII is effected, for example, by reducing themto the corresponding alcohols and then oxidizing the latter to form thealdehydes of the formula XII.

The reduction to the alcohols is effected, in particular, byhydrogenation of the corresponding acid halides or other activatedcarboxylic acid derivatives which are specified under process a), or byreacting activated carboxylic acid derivatives of the compounds of theformula XI, in particular anhydrides with organic carboxylic acids,preferably those which are obtained with haloformic acid esters, forexample isobutyl chloroformate (which are preferably obtained byreacting the compounds of the formula XI in the presence of basicamines, for example tri-lower-alkylamines, such as triethylamine, inorganic solvents, such as cyclic ethers, for example dioxane, attemperatures of between -50 and 80° C., preferably of between 0 and 50°C.) with complex hydrides, such as alkali metal borohydrides, forexample sodium borohydride, in aqueous solution in the presence orabsence of the last organic solvents to be used, at temperatures ofbetween -50 and 80° C., preferably of between 0 and 50° C. Thesubsequent oxidation of the resulting alcohols is preferably effectedusing those oxidizing agents which selectively convert the hydroxylgroup into an aldehyde group, for example chromic acid or itsderivatives, such as pyridinium chromate or tert-butyl chromate,dichromate/sulfuric acid, sulfur trioxide in the presence ofheterocyclic bases, such as pyridine/SO₃ (preferably dissolved indi-lower-alkyl sulfoxides, such as dimethyl sulfoxide, aromaticsolvents, such as toluene, or mixtures of these solvents), and alsonitric acid, manganese dioxide or selenium dioxide, in water, aqueous ororganic solvents, such as halogenated solvents, for example methylenechloride, carboxamides, such as dimethylformamide, and/or cyclic ethers,such as tetrahydrofuran, in the presence or absence of basic amines, forexample tri-lower-alkylamines, such as triethylamine, at temperatures offrom -70 to 100° C., preferably of from -70 to 50° C., or from -10 to50° C., for example as described in European Patent Application EP-A-0236 734, or by reaction with dicarbonyl halides, such as oxalylchloride, and di-lower-alkyl sulfoxides, such as dimethyl sulfoxide, ina halogenated hydrocarbon, such as dichloromethylene, in the presence ofa tertiary nitrogen base, such as triethylamine, at preferredtemperatures of from about -70 to 0° C., for example at about -60° C.

It is also possible directly to reduce the compounds of the formula XIto the aldehydes, for example by hydrogenation in the presence of apartially poisoned palladium catalyst, or by reducing the correspondingamino acid esters, for example the lower-alkyl esters, such as ethylesters, with complex hydrides, for example borohydrides, such as sodiumborohydride or, preferably, aluminium hydrides, for example lithiumaluminium hydride, lithium tri-(tert-butoxy)aluminium hydride or, inparticular, diisobutylaluminium hydride, in apolar solvents, for examplein hydrocarbons or aromatic solvents, such as toluene, at from -100 to0° C., preferably from -70 to -30° C., and first subsequently convertingthe products into the corresponding semicarbazones, for example usingthe corresponding acid salts of semicarbazones, such as semicarbazidehydrochloride, in aqueous solvent systems, such as alcohol/water, forexample ethanol/water, at temperatures of between -20 and 60° C.,preferably from 10 to 30° C., and then reacting the resultingsemicarbazone with a reactive aldehyde, for example formaldehyde, in aninert solvent, for example a polar organic solvent, for example acarboxamide, such as dimethylformamide, at temperatures of between -30and 60° C., preferably from 0 to 30° C., and then reacting with an acid,for example a strong mineral acid, such as hydrohalic acid, in aqueoussolution, in the absence or presence of the solvent which was previouslyused, at temperatures of between -40 and 50° C., preferably between -10and 30° C. The corresponding esters are obtained by reacting the aminoacids with the corresponding alcohols, for example ethanol, in analogywith the conditions used in the condensation under process b), forexample by reacting with inorganic acid halides, such as thionylchloride, in organic solvent mixtures, such as mixtures of aromatic andalcoholic solvents, for example toluene and ethanol, at temperatures ofbetween -50 and 50° C., preferably of between -10 and 20° C.

In order to synthesize the compounds of the formula III or III', thecompounds of the formula XII are then reacted with a reactivetetraalkylsilane, preferably a halomethyltri-lower-alkylsilane, such aschloromethyltrimethylsilane, in an inert solvent, for example an ether,such as diethyl ether, a cyclic ether, such as dioxane, or an ester,such as ethyl acetate, at temperatures of between -100 and 50° C.,preferably of between -65 and 40° C., with compounds of the formula##STR32## being obtained, in which R₆, R₇ and R₈ are lower alkyl, forexample methyl, and the remaining radicals are as defined above, theresulting compounds are converted, in the presence of a Lewis acid, suchas boron trifluoride ethyl etherate, in an inert solvent, in particulara halogenated hydrocarbon, such as methylene chloride or chloroform,with subsequent aftertreatment with an aqueous base, for example sodiumhydroxide solution, at temperatures of between -30 and 80° C., inparticular of between 0 and 50° C., with elimination and protectivegroup detachment, into olefinic compounds of the formula ##STR33## inwhich R₂ has the meanings specified for compounds of the formula I, anamino protective group Pa, for example tert-butoxycarbonyl, is onceagain introduced into the corresponding olefin, as described underprocess a) for the introduction of amino protective groups, inparticular using an acid anhydride in a chlorinated hydrocarbon, such asmethylene chloride or chloroform, at temperatures of between -50 and 80°C., in particular of between 0 and 35° C., with a protected amino-olefinof the formula ##STR34## being obtained in which the radicals are asdefined above, the double bond is converted into an oxirane, preferablystereoselectively using peroxides, in particular peroxycarboxylic acids,for example haloperbenzoic acid, such as m-chloroperbenzoic acid, in aninert organic solvent, preferably a halogenated hydrocarbon, such asmethylene chloride or chloroform, at temperatures of between -50 and 60°C., in particular of between -10 and 25° C., and, if required, adiastereomer resolution is undertaken, with epoxides of the formula##STR35## in which the radicals are as defined above, being obtained, asuitable malonic acid diester, for example dimethyl malonate or diethylmalonate, is added to the olefins concerned, for example by activatingthe methylene group of the malonic acid diester by means of an alkalimetal, for example sodium, in a polar, anhydrous solvent, such as analcohol, for example methanol or ethanol, at temperatures of between -50and 80° C., in particular between 0 and 35° C., and the solution istreated with an acid, for example carboxylic acid, such as citric acid,with a lactone of the formula ##STR36## in which R₉ is lower alkoxy, forexample methoxy or ethoxy, and the remaining radicals are as definedabove, being obtained, if desired R₂ is reduced to cyclohexyl in thosecompounds in which this radical is phenyl which is unsubstituted or issubstituted as described for compounds of the formula I, in particularby hydrogenation, preferably in the presence of catalysts, such asprecious metal oxides, for example mixtures of Rh(III)/Pt(VI) oxides (inaccordance with Nishimura), preferably in polar solvents, such asalcohols, for example methanol, under standard pressure or up to 5 bar,preferably under standard pressure, at temperatures of from -20 to 50°C., preferably from 10 to 35° C., the compounds of the formula XVIIwhich are obtained directly or after the hydrogenation are reacted witha reagent which introduces the R₃ --CH₂ -- radical, for example of theformula

    R.sub.3 --CH.sub.2 --W                                     (XVII),

in which R₃ has the meanings specified for compounds of the formula Iand W is a nucleofugic leaving group, preferably selected from hydroxylwhich is esterified with a strong inorganic or organic acid, such ashydroxyl which is esterified with a mineral acid, for example hydrohalicacid, such as hydrochloric acid, hydrobromic acid or hydriodic acid,with a strong organic sulfonic acid, such as a lower-alkanesulfonic acidwhich is unsubstituted or substituted, for example, by halogen, such asfluorine, or an aromatic sulfonic acid, for example a benzenesulfonicacid which is unsubstituted or substituted by lower alkyl, such asmethyl, halogen, such as bromine, and/or nitro, for example amethanesulfonic, trimethanesulfonic or p-toluenesulfonic acid, andhydroxyl which is esterified with hydrazoic acid, in particular bromide,in an anhydrous polar solvent, for example an alcohol, such as ethanol,in the presence of an alkali metal, for example sodium, at temperaturesof between -50 and 80° C., preferably of between 0 and 35° C., to formcompounds of the formula ##STR37## in which the radicals are as definedabove, the compounds of the formula XIX are hydrolysed anddecarboxylated, for example by hydrolysis with a base, such as an alkalimetal hydroxide, for example lithium hydroxide or NaOH, at temperaturesof between -50 and 80° C., preferably of between about 0 and 35° C., inan organic solvent, for example an ether, such as 1,2-dimethoxyethane,or an alcohol, such as ethanol, and subsequent decarboxylation byheating in an inert solvent, preferably a hydrocarbon, for example anaromatic hydrocarbon, such as toluene, at temperatures of between 40 and120° C., preferably of between 70 and 120° C., with a compound of theformula ##STR38## in which the radicals as defined above, beingobtained, the resulting (R,S,S) and (S,S,S) isomers are resolved bycolumn chromatography, the (R,S,S) isomer is reused and, for opening thelactone ring, is reacted with a base, such as an alkali metal hydroxide,for example lithium hydroxide or sodium hydroxide, in an inert solvent,such as an ether, for example dimethoxyethane, or an alcohol, such asethanol, to form a compound of the formula ##STR39## in which theradicals are as defined above, an hydroxyl protective group Py, forexample one of the hydroxyl protective groups specified under processa), in particular a tri-lower-alkylsilyl group, is introduced, under theconditions specified there, into the resulting compound using thecorresponding halo-tri-lower-alkylsilane, for exampletert-butyldimethylchlorosilane, in a polar solvent, such as adi-lower-alikyl-lower-alkanoylamide, such as dimethylformamide, in thepresence of a sterically hindered amino compound, such as a cyclicamine, for example imidazole, at temperatures of from -50 to 80,preferably from 0 to 35° C., and the carboxyl group which is alsosilylated art the same time is set free once again by reaction with abasic metal salt, in particular an alkali metal hydroxide or alkalimetal hydrogen carbonate or, preferably,

an alkali metal carbonate, such as potassium carbonate, preferably in analcohol, such as methanol or ethanol, a cyclic ether, such astetrahydrofuran, in water or, in particular, a mixture of 2 or 3 ofthese solvents, at preferred temperatures of between 0 and 50° C., inparticular of from 10 to 35° C., with a compound of the formula##STR40## being obtained, in which the radicals are as defined above,and the compounds of the formula III or III' having the radicals givenunder process a) are prepared, for example, from one of the compounds ofthe formula XXII by condensation with a compound of the formula VI, inwhich the radicals have the meanings given under process c), underconditions which are analogous to those given for process a), inparticular by in-situ reaction in the presence of a condensing agent,such as N,N-dicyclohexylcarbodiimide, ethyl cyanophosphonate,benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphateor 0-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate,a sterically hindered amine, such as triethylamine orN-methylmorpholine, and, if desired, a racemization-preventing compound,such as 1-hydroxybenzotriazole, in a polar solvent, preferably an acidamide, for example a di-lower-alkylamino-lower-alkanoylamide, such asdimethylformamide, a cyclic ether, such as tetrahydrofuran, or anitrile, such as acetonitrile, at preferred temperatures of between -50and 80° C., in particular of between 0 and 35° C., if desired underprotective gas, such as argon or nitrogen, and by the subsequentdetachment of the protective group Pa under analogous conditions, asdescribed under process f), (provided Pa is not a radical whichcorresponds to the radical R₁ having the meanings presented above forcompounds of the formula I, which would lead directly to compounds ofthe formula I) and finally, if desired, the detachment of Py and/orfurther protective groups under analogous conditions to those describedunder process f). In order to prepare the compounds of the formula IIIor III', it is also possible successively to condense the compounds ofthe formula XXII with compounds which introduce the radicals--HN--(CHR₄)--CO-- (starting material: the corresponding amino acids H₂N--(CHR₄)--COOH) and --NH--CH₂ --(CH₂)_(n) --O--R₅ (starting material:the corresponding amino compound H₂ N--CH₂ --(CH₂)_(n) --O--R₅) of thecompound of the formula III or III', under conditions which areanalogous to those specified for process a), preferably by reacting acompound which is analogous to the compound of the formula (i) V or V',(ii) VII or VII' or (iii) IX or IX', in which hydrogen is present inplace of R₁, with a compound of the formula (i) VI or VI' (correspondsto a compound of the formula XXII in which Pa=hydrogen), (ii) VIII or(iii) X, where the remaining radicals in each case have the specifiedmeanings and the starting materials can also be present as the reactivederivatives, in analogy with the conditions specified under (i) processc), (ii) process d) or (iii) process e), with it being possible todetach the protective group Py from compounds of the formula III or III'using one of the methods described under process f).

The following route can also be taken for preparing a compound of theformula XX from an abovementioned compound of the formula XVII:

Hydrolysis of a racemic compound of the formula XVII (which can beprepared from the racemate of a compound of the formula XV via thecorresponding racemate of a compound of the formula XVI) anddecarboxylation under conditions analogous to those for the hydrolysisand decarboxylation of compounds of the formula XIX leads to a compoundwhich is analogous to the compound of the formula XIX in which, however,the radicals R₃ --CH₂ -- and R₉ --(C═O)-- are missing (in both cases, ahydrogen atom is present instead) and which is present as a racemate (oras a diastereomer mixture providing an additional centre of asymmetry ispresent in R₃ and/or R₉); this latter compound is subsequently reactedwith a compound of the formula XVIII, as defined above, in which W isone of the abovementioned nucleofugic leaving groups, in particularhalo, such as iodine or, preferably, bromine or chlorine, by firstdeprotonating it in the presence of a strong base, such as an alkalimetal bis(tri-lower-alkylsilyl)amide, for example lithiumbis(trimethylsilyl)amide, and then alkylating it with the compound ofthe formnula R₃ --CH₂ --W (preferably obtaining the 1'(S),3(R)--(R₃--CH₂ --),5(S)!-- and the 1'(R),3(S)--(R₃ --CH₂ --),5(R)! compounds ofthe formula XX, i.e. a racemate as regards the said asymmetric carbonatoms).

The abovementioned compounds of the formula XIV can also be present inthe (R,S) configuration instead of the indicated (S) configuration atthe carbon atom carrying the --NH₂ radical, while the compounds of theformulae XI, XII and XIII and, in particular, those of the formulae XV,XVI, XVII, XIX, XX, XXI and/or XXII can also be present in the (R,S)configuration instead of the (S) configuration at the carbon atomcarrying the Pa--NH-- radical. The abovementioned compounds of theformulae XV, XVI and XVII can also be present as racemates. Othermixtures of the optical antipodes of the indicated formulae are alsopossible. Corresponding compounds of the formula V, for example, can beobtained from these racemates or mixtures (for example racemates orantipode mixtures if RI does not contain any cenrues of assymetry), sothat, in this way, compounds of the formula I or I' are accessible inwhich either the carbon atom carrying R₂ --CH₂ -- is in the (S)configuration, the carbon atom carrying HO-- is in the (S) configurationand the carbon atom carrying R₃ --CH₂ -- is in the (R) configuration(2R,4S,5S), or the said carbon atoms h ave the opposite configuration(2S,4R,5R); or else mixtures of compounds of the formula V or I ar epresent which have both these configurations. Corresponding racemicmixtures or diastereomer mixtures can be dissolved at suitable stages(preferably) into individual isomers.

Compounds of the formula XX, in which the radicals have the saidmeanings, are prepared from compounds of the formula XII, in which theradicals have the said meanings, by reacting the aldehydes of theformula XII with 2-halopropionic acid esters, in particular lower-alkyl2-iodopropionates, such as ethyl 2-iodopropionate, with the compounds ofthe formula ##STR41## being obtained , in which the radicals have thesaid meanings and in which the carbon atom carrying the Pa--NH-- radicalcan also, alternatively, be present, for example, in the (R,S)configuration.

The reaction initially takes place with the formation of the homoenolateof the 2-halopropionic acid-lower-alkyl(such as ethyl) ester in thepresence of a mixture of Zn/Cu in a di-lower-aikyl-lower-alkanoylamide,such as dimethylacetamide, or of an aromatic hydrocarbon, such astoluene, or mixtures thereof, at temperatures of between 0 and 100° C.,in particular of between 20 and 80° C., if desired under protective gas,such as argon or N₂. In a subsequent reaction mixture, a suitabletetra-lower-alkyl orthotitanate, such as tetraisopropyl orthotitanate,is treated, preferably under a protective gas, such as nitrogen orargon, in an aromatic solvent, such as toluene or xylene, in thepresence of a halohydrocarbon, such as methylene chloride, with atitanium tetrahalide, such as titanium tetrachloride, at from -50 to 50°C., preferably at from -40 to 25° C., and the mixture is stirred, withthe corresponding dihalo-titanium-di-lower-alkylate or, preferably, thetrihalo-titanium-lower-alkylate, in particular trichlorotitaniumdiisopropylate, being formed. The Zn-homoenolate solution is addeddropwise to the latter at temperatures of between -50 and 0° C., inparticular of from -40 to -25° C., and the aldehyde of the formula XIIin a halohydrocarbon, for example methylene chloride, is subsequentlyadded dropwise, with the reaction taking place at from -50 to 30° C.,preferably at from about -40 to 5° C., with the formation of thelower-alkyl-(in particular ethyl) ester precursor, in particular theethyl ester, of the compound of the formula XXIII. This ester is thenhydrolysed and cyclized with the formation of the compound of theformula XXIII, as defined above, preferably in an organic solvent, suchas an aromatic compound, for example in toluene or xylene, in thepresence of an acid, such as a carboxylic acid, for example acetic acid,at temperatures of between 20° C. and the boiling point of the reactionmixture, in particular between 70 and 100° C. If necessary, thediastereomers are separated, for example by means of chromatography, forexample on silica gel using an organic solvent mixture, such as amixture of alkane and ester, such as lower alkane andlower-alkyl-lower-alkanoyl ester, such as hexane/ethyl acetate.

The corresponding compound of the formula XX is then obtained from thecompound of the formula XXIII by deprotonation with a strong base, withthe formation of the carbanion at the α-carbon next to the oxo group ofthe lactone, and subsequent nucleophilic substitution of the W radicalof a compound of the formula XVIII, in which R₃ and W are defined asabove in association with the preparation of compounds of the formulaXIX (W is, in particular, bromo), with the reaction preferably leadingstereoselectively to the (R) configuration at the carbon atom in thecompound of the formula XX which carries the R₃ --CH₂ -- radical. Thereaction with the strong base, in particular with an alkalimetal-organosilicon amide compound, for example an alkali metalbis(tri-lower-alkylsilyl)amide, such as lithiumbis(trimethylsilyl)amide, or else an alkali metal di-lower-alkylamide,such as lithium diisopropylamide, is preferably carried out in an inertorganic solvent, in particular an ether, for example a cyclic ether,such as tetrahydrofuran, or1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), or mixturesof these solvents, at temperatures of between -100 and 0° C., preferablyof between -78 and -50° C., while the nucleophilic substitution iscarried out in situ by adding the compound of the formula R₃ --CH₂ --Win the same solvent and at temperatures of between -100 and 0° C.,preferably of between -60 and -40° C.

A compound of the formula XIV, in which the radicals have the saidmeanings, and in which the carbon atom carrying the --NH₂ group ispreferably in the (R,S) configuration, can also be obtained byconverting a formic acid ester, for example lower-alkyl formate, such asethyl formate, into formic acid allylamide by reacting it withallylamine at temperatures of between 20 and 70° C., in particular ofbetween 50 and 60° C. This amide is then dehydrated under a protectivegas, such as nitrogen or argon, preferably using an acid halide, such asphosphor-us oxychloride, phosgene or, in particular, an organic sulfonylhalide, for example an arylsulfonyl chloride, such as toluenesulfonylchloride, in the presence of a base, for example a tri-lower-alkylamine,such as triethylamine, or, in particular, a mono- or bi-cyclic amine,such as pyridine or quinoline, at temperatures of between 50 and 100°C., in particular of between about 80 and about 100° C. This results inthe formation of allyl isocyanide, which is converted into thecorresponding lithium salt by reaction with an organolithium salt, forexample lower-alkyllithium, such as n-butyllithium, with the reactionpreferably being carried out in an inert organic solvent, in particularan ether , such as dioxane or diethyl ether, or an alkane, for examplehexane, or a mixture of these solvents, at temperatures of from --120 to--50, in particular of from about -100 to -70° C. The lithium salt whichhas been formed is then reacted in situ with a compound of the formulaR₂ --CH₂ --W, in which R₂ has the meanings specified for compounds ofthe, formula I and W has the meanings specified above for compounds ofthe formula XVIII, in particular bromine,, preferably by adding R₂ --CH₂--W dropwise in an organic solvent, for example an ether, such astetrahydrofuran, at the temperatures mentioned immediately above, andthen warming to from 0 to 50° C., preferably to from 20 to 30° C. Thisresults in the formation of an isocyanide of the formula ##STR42## inwhich the radicals have the said meanings. The compound of the formulaXXIV is subsequently hydrolysed, preferably in aqueous solution to whichan acid is added, for example in aqueous hydrohalic acid, such ashydrochloric acid, in particular in concentrated hydrochloric acid, attemperatures of between -20 and 30° C., in particular of between about 0and 10° C., and the compound of the formula XIV is obtained, in whichthe radicals are defined as most recently above and in which the carbonatom carrying the --NH₂ group is preferably in the (R,S) configuration.

Amino compounds of the formula IIIa or IIIa', or their reactivederivatives, are known or can be prepared by methods which are known perse, for example by condensing amino acids of the formula H--B₁ --OH, inwhich B₁ has the meanings specified for compounds of the formula III orIII', or reactive derivatives thereof, with amino compounds of theformula III or III', or reactive derivatives thereof, with the reactivederivatives and the condensation conditions being analogous to thosedescribed under process a).

Compounds of the formula V or V' are prepared, for example, provided theprotective group Pa in formula XXI or XXII does not correspond directlyto an R₁ radical, from the amino compounds of the formula XXI or XXII,for example by introducing a carboxyl protective group, as describedunder process a), and detaching the protective group Pa, as describedunder process f), by condensation with a carboxylic acid of the formulaR₁ --OH, or a reactive derivative thereof, in which the radicals havethe meanings specified for compounds of the formula I, under conditionswhich are analogous to the condensation conditions specified for processa).

Compounds of the formula XXA or XXA' are prepared, for example, providedthe protective group Pa in the formula XX does not correspond directlyto an R₁ radical, from the γ-lactone compounds of the formula XX(preferably from the (R,S,S) isomer), for example by detaching theprotective group Pa, as described under process f), by condensation witha carboxylic acid of the formula R₁ --OH, or a reactive derivativethereof, in which the radicals have the meanings specified for compoundsof the formula I, under conditions which are analogous to thecondensation conditions specified for process a).

Compounds of the formula VI (or VI') are prepared, for example, from thecorresponding amino acids of the formula ##STR43## (in particular of theformula ##STR44## in which the radicals have the said meanings, orreactive acid derivatives thereof, and the amino component of dueformula VIII, in which the radicals are in each case defined as above,or reactive derivatives thereof, by condensation in analogy with themethod described under process a) and, if desired, using analogousreactive derivatives.

Compounds of the formula VII (or VII') can be prepared, for example,from compounds of the formula V (or V') by condensation with an aminoacid of the formula XXV (or XXV'), as defined immediately above, whichintroduces the radical --NH--CH(R₄)--COOH. The reaction is carried outin analogy with the conditions described under process a) using thecorresponding free compounds or their reactive derivatives; or they canbe prepared from compounds of the formula XXA (or XXA') by condensationwith an amino acid of the formula XXV (or XXV'), as defined immediatelyabove, which introduces the radical --NH--CH(R₄)--COOH. The reaction iscarried out in analogy with the conditions described under process c)using the corresponding γ-lactones of the formula XXA, in particularXXA'.

The amino compound of the formula VIII is known or is prepared bymethods which are known per se.

Compounds of the formula IX (or IX') are known or can be prepared bymethods which are known per se, and are obtained, for example, by thecondensation of a compound of the formula VII (or VII'), in which theradicals have the said meanings, and an (if necessaryhydroxyl-protected) amine of the formula

    H.sub.2 N--CH.sub.2 --(CH.sub.2).sub.n --OH                (XXVI),

or a reactive derivative thereof, in which n has the meanings given forcompounds of the formula I, under reaction conditions analogous to thosedescribed under process a).

Compounds of the formula X or Xa are known, are commercially available,or can be prepared by methods which are known per se.

Compounds of the formula XVIII and the formula R₂ --CH₂ --W are known orcan be prepared by methods which are known per se, or they can beobtained commercially. As an example, mention may be made of thepreparation of a compound of the formula XVIII or R₂ --CH₂ --W, in whichW is Br or I, by reacting the corresponding precursor, in which W is Cl,with an alkali metal iodide or bromide, such as NaI, for example inketones, such as a lower-alkanone, for example acetone, at temperaturesof between 0 and 50° C., in particular room temperature, or with aphosphorus tri- or penta-iodide or -bromide, such as PBr₃, for examplein hydrocarbons, for example an aromatic hydrocarbon, such as toluene,at preferred temperatures of between 0 and 40° C., for example at roomtemperature. The precursor (W═Cl) is commercially obtainable, is knownor can be prepared by methods which are known per se.

For example, a precursor, in which a hydroxyl group is present in placeof the Cl (═W), can be converted into the corresponding chlorinatedcompound by reaction with PCl₃, PCl₅ or, in particular, SOCl₂, in thepresence of a tertiary nitrogen base, for example polyhunig base orpyridine, in suitable solvents, for example an ether, such as diethylether, or a halohydrocarbon, such as methylene chloride or chloroform,at preferred temperatures of between -10 and 30° C., preferably ofbetween 0 and 25° C. The precursors in which a hydroxyl group is presentin place of W are known, can be prepared by methods which are known perse, or are commercially available.

The remaining starting compounds are known, are prepared by methodswhich are known per se, and/or are commercially available.

The following intermediates, which are specified under (i) to (iv) arealso, in particular, a preferred subject-matter of the presentinvention:

(i) a compound of the formula XIXA, ##STR45## (in particular of theformula XIXA' ##STR46## in which Q is hydrogen; an amino protectivegroup, preferably an amino protective group Pa, as defined for compoundsof the formula XI (in particular one of the amino protective groupsspecified under process a)); or a radical R₁, as defined for compoundsof the formula I, apart from those radicals which come within thedefinition of the protective group Pa;

R₂ has one of the meanings specified in the definition of compounds ofthe formula I;

R₃ is phenyl which is trisubstituted by radicals selected from loweralkyl, lower alkoxy and halogen, or is lower-alkylenedioxyphenyl, inparticular 2,3,4-tri-lower-alkoxyphenyl, especially2,3,4-trimethoxyphenyl; and

R₉ is lower alkoxy, for example methoxy or ethoxy,

or a salt thereof, provided salt-fonning groups are present.

A compound of the formula XIXA, in particular XIXA', is particularlypreferred in which Q is hydrogen or, in particular, is1-phenyl-lower-alkoxycarbonyl, in particular benzyloxycarbonyl,1-phenyl-lower-alkyl, in particular benzyl, or is primarilylower-alkoxycarbonyl, such as tert-butoxycarbonyl;

R₂ is cyclohexyl or, in particular, phenyl;

R₃ is 2,3,4-tri-lower-alkoxyphenyl, in particular2,3,4-trimethoxyphenyl;

and R₉ is lower alkoxy, such as methoxy or ethoxy;

or a salt thereof, provided salt-forming groups are present.

The compounds of the formula XIXA or XIXA' either correspond directly tothe compounds of the formula XIX, when Q is an amino protective groupPa, or they can be prepared from these compounds by protective groupdetachment in analogy with the conditions described under process f)(yields compounds of the formula XIXA or XIXA' in which Q=H) and, ifdesired, introduction of an R₁ radical with an acid of the formula II,as defined above for process a), under analogous conditions to thosespecified under process a).

(ii) A compound of the formula XXA ##STR47## (in particular of theformula XXA' ##STR48## especially of the formula XXA" ##STR49## in whichQ is hydrogen; an amino protective group, preferably an amino protectivegroup Pa, as defined for compounds of the formula XI (in particular oneof the amino protective groups specified under process a)); or an R₁radical, as defined for compounds of the formula I, apart from thoseradicals which come within the definition of the protective group Pa;

R₂ has one of the meanings specified in the definition of compounds ofthe formula I; and

R₃ is phenyl which is trisubstituted by radicals selected from loweralkyl, lower alkoxy and halogen, or is lower-alkylenedioxyphenyl, inparticular 2,3,4-tri-lower-alkoxyphenyl, especially2,3,4-trimethoxyphenyl;

or a salt thereof, provided salt-forming groups are present.

A compound of the formula XXA, in particular XXA', especially XXA", isparticularly preferred in which Q is hydrogen or, in particular, is1-phenyl-lower-alkoxycarbonyl, in particular benzyloxycarbonyl,1-phenyl-lower-alkyl, in particular benzyl, or is, primarily,lower-alkoxycarbonyl, such as tert-butoxycarbonyl;

R₂ is cyclohexyl or, in particular, phenyl; and

R₃ is 2,3,4-tri-lower-alkoxyphenyl, in particular is2,3,4-trimethoxyphenyl;

or a salt thereof, provided salt-forming groups are present.

A compound of the formula XXA" is preferred which has the designation5(S)- 1 (S)-(Boc-amino)-2-cyclohexylethyl!-3(R)-(2,3,4-trimethoxyphenylmethyl)-dihydrofuran-2-(3H)-one.

A compound of the formula XXA" is very particularly preferred which hasthe designation 5(S)-1(S)-(Boc-amino)-2-phenylethyl!-3(R)-(2,3,4-trimethoxyphenylmethyl)-dihydrofuran-2-(3H)-one.

The compounds of the formula XXA or XXA' or XXA" can be prepared fromthe compounds of the formula XIX or XIXA in an analogous manner to thatdescribed above for the conversion of compounds of the formula XIX intothose of the formula XX; or they correspond directly to the compounds ofthe formula XX when Q is an amino protective group Pa, or they can beprepared directly from these compounds by protective group detachment inanalogy with the conditions specified under process f) (yields compoundsof the formula XIXA or XIXA' in which Q=H) and, if desired, introductionof an R₁ radical with an acid of the formula II, as defined above forprocess a), under conditions which are analogous to those specifiedunder process a).

iii) A compound of the formula VA ##STR50## (in particular of theformula VA' ##STR51## in which Q is hydrogen; an amino protective group,preferably an amino protective group Pa, as defined for compounds of theformula XI (in particular one of the amino protective groups specifiedunder process a)); or an R₁ radical, as defined for compounds of theformula I, apart from those radicals which come within the definition ofthe protective group Pa;

R₂ has one of the meanings specified in the definition of compounds ofthe formula I;

R₃ is phenyl which is trisubstituted by radicals selected from loweralkyl, lower alkoxy and halogen, or is lower-alkylenedioxyphenyl, inparticular is 2,3,4-tri-lower-alkoxyphenyl, especially2,3,4-trimethoxyphenyl;

Py* is hydrogen or a hydroxyl protective group, preferably one of theprotective groups specified under process a), in particulartri-lower-alkylsilyl, such as tert-butyldimethylsilyl; and

E is hydroxy or a carboxyl protective group, preferably as defined underprocess a), in particular lower-alkoxy, such as methoxy, ethoxy ortert-butoxy, or tri-lower-alkylsilyloxy, in particulartert-butyldimethylsilyloxy, or the radical --(C═O)--E is a reactivederivative of a carboxylic group, in particular is a carboxylic group inthe form of an activated ester, of a reactive anhydride or else of areactive cyclic amide, preferably in an analogous manner to thatdescribed for reactive derivatives of compounds of the formula II underprocess a);

or a salt thereof, provided salt-forming groups are present.

A compound of the formula XXA, in particular XXA', especially XXA", isparticularly preferred in which

Q is hydrogen or, in particular, is 1-phenyl-lower-alkoxycarbonyl, inparticular benzyloxycarbonyl, 1-phenyl-lower-alkyl, in particularbenzyl, or, primarily, is lower-alkoxycarbonyl, such astert-butoxycarbonyl;

R₂ is cyclohexyl or, in particular, phenyl;

R₃ is 2,3,4-tri-lower-alkoxyphenyl, in particular2,3,4-trimethoxyphenyl;

Py* is hydrogen or a hydroxyl protective group, preferably one of thoseprotective groups specified under process a), in particulartri-lower-alkylsilyl, such as tert-butyldimethylsilyl; and

E is hydroxyl or a carboxyl protective group, preferably as definedunder process a), in particular lower alkoxy, such as methoxy, ethoxy ortert-butoxy, or tri-lower-alkylsilyloxy, in particulartert-butyldimethylsilyloxy, or the radical --(C═O)--E is a reactivederivative of a carboxyl group, in particular is a carboxyl group in theform of an activated ester, of a reactive anhydride or else of areactive cyclic amide, preferably in an analogous manner to thatdescribed for reactive derivatives of compounds of the formula II underprocess a); in particular is hydroxyl and lower alkoxy;

or a salt thereof, provided salt-forming groups are present.

A compound of the formula VA' is preferred which has the designation5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!-hexanoic acid, or a salt thereof.

A compound of the formula VA' is also preferred which has thedesignation5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-2,3,4-trimethoxyphenyl)methyl!hexanoic acid or a salt thereof.

A compound of the formula VA' is very particularly preferred which hasthe designation 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoic acid, or a salt thereof (inparticular an alkali metal salt, for example the sodium salt, which canbe very efficiently crystallized).

A compound of the formula VA' is likewise very particularly preferredwhich has the designation5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoic acid, or a salt thereof.

Compounds of the formula VA and VA' correspond to compounds of theformula V and V', respectively, whose preparation has already beendescribed above.

The compounds of the formula VA and VA' correspond directly to thecompounds of the formula V and V', respectively, when Q is an aminoprotective group Pa, Py* is hydrogen and E is hydroxyl; the remainingcorresponding compounds of the formula VA and VA', in which at least oneof the radicals Py* or E has a meaning specified in the definition ofcompounds of the formula VA and VA' which is different from thosementioned above, can be obtained from these latter compounds byprotective group introduction, for example as described in associationwith the introduction of Py in compounds of the formula XXI in order toprepare compounds of the formula XXII, or as described under process a),or by the preparation of reactive carboxylic acid derivatives, asdescribed under process a). The corresponding compounds in which Q has ameaning other than Pa can be prepared from these compounds of theformula VA and VA', or those of the formula V and V', by protectivegroup detachment in analogy with the conditions specified under processf) (yields compounds of the formula VA and VA' in which Q=H) and, ifdesired, introduction of an R₁ radical with an acid of the formula II,as defined above for process a), under conditions which are analogous tothose specified under process a).

And/or:

(iv) A compound of the formula VIIA ##STR52## (in particular of theformula VIIA') ##STR53## in which R₁ has the meanings specified forcompounds of the formula I,

R₂ has one of the meanings specified in association with the definitionof compounds of the formula I;

R₃ is phenyl which is trisubstituted by radicals selected from loweralkyl, lower alkoxy and halogen, or is lower-alkylenedioxyphenyl, inparticular is 2,3,4-tri-lower-alkoxyphenyl, especially2,3,4-trimethoxyphenyl;

Py* is hydrogen or a hydroxyl protective group, preferably one of thosespecified under process a), in particular tri-lower-alkylsilyl, such astert-butyldimethylsilyl; and

E is hydroxyl or a carboxyl protective group, preferably as definedunder process a), in particular lower alkoxy, such as methoxy, ethoxy ortert-butoxy, or tri-lower-alkylsilyloxy, in particulartert-butyldimethylsilyloxy, or the radical --(C═O)--E is a reactivederivative of a carboxylic group, in particular is a carboxylic group inthe form of an activated ester, of a reactive anhydride or else of areactive cyclic amide, preferably in an analogous manner to thatdescribed under process a) for reactive derivatives of compounds of theformula II;

or a salt thereof, provided salt-forming groups are present.

A compound of the formula VIIA, in particular VIIA', is particularlypreferred in which

R₁ is phenyl-lower-alkoxycarbonyl, in particular islower-alkoxycarbonyl, such as tert-butoxycarbonyl;

R₂ is cyclohexyl or, in particular, phenyl;

R₃ is 2,3,4-tri-lower-alkoxyphenyl, in particular2,3,4-trimethoxyphenyl;

Py* is hydrogen or a hydroxyl protective group, preferably one of thosespecified under process a), in particular tri-lower-alkylsilyl, such astert-butyldimethylsilyl; and

E is hydroxyl or a carboxyl protective group, preferably as definedunder process a), in particular lower alkoxy, such as methoxy, ethoxy ortert-butoxy, or tri-lower-alkylsilyloxy, in particulartert-butyldimethylsilyloxy, or the radical --(C═O)--E is a reactivederivative of a carboxylic group, in particular is a carboxylic group inthe form of an activated ester, of a reactive anhydride or else of areactive cyclic amide, preferably in an analogous manner to thatdescribed under process a) for reactive derivatives of compounds of theformula II; in particular is hydroxyl and lower alkoxy;

or a salt thereof, provided salt-forming groups are present.

The compound of the formula VIIA' is particularly preferred which hasthe designation5(S)-(Boc-amino)-4(S)-(tert-butyidimethylsilyloxy)-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoic acid, or a salt thereof.

The compounds of the formula VIIA and VIIA' either correspond tocompounds of the formula VII and VII', respectively, and can be preparedas described above (when Py*=H, and E=OH), or can be prepared (when Py*has one of the said meanings other than hydrogen and/or E has one of thesaid meanings other than hydroxyl) from compounds of the formula VII andVII', respectively, by protective group introduction, for example asdescribed in association with the introduction of Py in compounds of theformula XXI in order to prepare compounds of the formula XXII, or asdescribed under process a), or by the preparation of reactive carboxylicacid derivatives, as described under process a).

The following applies generally to all processes mentioned above andbelow:

As a consequence of the close relationship between the compounds of theformula I and their salts and starting materials (starting compounds andintermediates) in free form and in the form of their salts, the freecompounds and/or their salts are to be understood, both above and below,as meaning, analogously and expediently, where appropriate, thecorresponding salts and/or the free compounds as well.

All the above-listed process steps can be carried out under reactionconditions which are known per se, preferably under those which havebeen specifically specified, in the absence or, customarily, thepresence of solvents or diluents, preferably those which are inerttowards the reagents employed and dissolve the latter, in the absence orpresence of catalysts, condensing agents or neutralizing agents, forexample ion exchangers, such as cation exchangers, for example in the H⁺form, in each case depending on the nature of the reaction and/or of thereagent, at decreased, normal or increased temperature, for example in atemperature range of from about -100° C. to about 190° C., preferablyfrom about -80° C. to about 150° C., for example at from -80 to -60° C.,at room temperature, at from -20 to 40° C., or at reflux temperature,under atmospheric pressure or in a closed vessel, as desired underreduced or increased pressure, in an inert atmosphere, for example underan argon or nitrogen atmosphere, and/or with the exclusion of light.

If desired, isomeric mixtures which arise in any of the reaction stagescan be resolved into the individual isomers, for example diastereomersor enantiomers, or into arbitrary mixtures of isomers, for exampleracemates or diastereomer mixtures, for example in analogy with themethods which are described under the "additional process measures".

In certain cases, for example in the case of hydrogenations, it ispossible to achieve stereoselective reactions thereby, for example,facilitating the isolation of individual isomers.

The solvents from which those can be selected which are suitable foreach respective reaction include, for example, water, esters, such aslower-alkyl-lower-alkanoates, for example diethyl acetate, ethers, suchas aliphatic ethers, for example diethyl ether or 1,2-dimethoxyethane,or cyclic ethers, for example tetrahydrofuran, liquid aromatichydrocarbons, such as benzene, toluene or o-, m- or p-xylene, liquidacyclic hydrocarbons, such as hexane or heptane, alcohols, such asmethanol, ethanol or 1- or 2-propanol, nitriles, such as acetonitrile,halohydrocarbons, such as methylene chloride or chloroform, acid amides,such as dimethyl formamide or dimethylacetamide, ketones, such aslower-alkanones, for example acetone, heterocyclic solvents, for examplebases, such as heterocyclic nitrogen bases, for example pyridine, or1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (DMPU), carboxylicacids, such as acetic acid or formic acid, carboxylic anhydrides, suchas lower-alkanoic anhydrides, for example acetic anhydride, cyclic,linear or branched hydrocarbons, such as cyclohexane, hexane orisopentane, or mixtures of these solvents, for example aqueoussolutions, unless otherwise indicated in the description of theprocesses. Solvent mixtures of this nature can also be used in theworking-up, for example by chromatography or partition.

The compounds, including their salts, may also be obtained in the formof hydrates, or their crystals may, for example, include the solventused for the crystallization.

The working-up after reactions is carried out in accordance with methodswhich are known per se, preferably in analogy with the methods describedin the examples.

The invention also relates to those embodiments of the process in whicha compound which is obtainable as an intermediate at an arbitraryprocess stage is used as the starting material, and the missing processsteps are then carried out, or in which a starting compound is usedwhich is formed under the reaction conditions or is in the form of aderivative, for example in protected form or as a salt, or a compoundwhich can be obtained in accordance with the novel process is producedunder the process conditions and subjected to further processing insitu. In the process of the present invention, those starting compoundsare preferably employed which lead to the compounds which were describedat the outset as being particularly valuable. Reaction conditions areprimarily preferred which are analogous to those specified in theexamples.

Insofar as necessary or desired, protected starting compounds can beemployed at all process stages, and the protective groups can be removedat suitable reaction stages.

Protective groups, their introduction and their release are as describedunder processes a) and f).

EXAMPLES

The following examples serve to illustrate the invention but do not, inany way, restrict its scope.

Temperatures are given in degrees centigrade (° C.).

If no temperature is given, the reactions mentioned below take place atapproximately room temperature. The R_(f) values, which indicate theratio of the distance migrated by the particular substance to thedistance migrated by the eluent front, are determined by thin layerchromatography (TLC) on silica gel thin layer plates (Merck, Darmstadt,FRG) using the following solvent systems:

TLC eluent systems:

    ______________________________________    TLC eluent systems:    ______________________________________    A      Ethyl acetate    B      Methylene chloride/methanol                                 9:1    C      Hexane/ethyl acetate  1:1    D      Hexane/ethyl acetate  2:1    E      Hexane/ethyl acetate  3:1    F      Methylene chloride/methanol                                 12:1    G      Hexane/ethyl acetate  6:1    H      Methylene chloride/THF                                 2:1    I      Methylene chloride/ether                                 25:1    J      Hexane/ethyl acetate  1:2    K      Chloroform/methanol/water/acetic acid                                 85:13:1.5:0.5    L      Methylene chloride/methanol                                 10:1    M      Methylene chloride/methanol                                 15:1    N      Ethyl acetate/methanol                                 9:1    O      Methylene chloride/ethanol                                 10:1    P      Methylene chloride/ethyl acetate/                                 30:20:1           ethanol    Q      Toluene/ethyl acetate 9:1    R      Methylene chloride/THF                                 4:1    ______________________________________

The abbreviation "R_(f) (A)" means, for example, that the R_(f) valuewas determined in the solvent system A. The ratio of the quantities ofsolvents with respect to each other is always given in parts by volume(v/v). Quantity ratios are also given in parts by volume when definingthe mobile solvent systems for the column chromatography.

Part of the abovementioned letter code for TLC eluents is also used, forexample, for indicating eluents in column chromatography.

Medium pressure chromatography:

Phase: LiChroprep® Si 60 (Merck, Dietikon/Switzerland); pressure: 10-15bar.

HPLC gadients:

    ______________________________________    HPLC gradients:    ______________________________________    I            20% → 100% a) into b) over 35 min    II           20% → 100% a) into b) over 20 min    III          5% → 40% a) into b) over 15 min    ______________________________________

Eluent a): acetonitrile +0.05% TFA; eluent b): water+0.05% TFA. Column(250×4.6 mm) filled with C₁₈ -Nucleosil® reversed-phase material (silicagel, of 5 μm average particle size, which is covalently derivatized withoctadecylsilanes, Macherey & Nagel, Duren, FRG). Detection by UVabsorption at 215 nm. The retention times (t_(Ret)) are given inminutes. Flow speed, 1 m/min.

Mass spectroscopic measurements are as a rule obtained by the fast-atombombardment method. Unless otherwise indicated, the mass values relateto the protonated molecule ion (M+H)⁺.

The values for IR spectra are given in cm⁻¹, with the relevant solventbeing given in round brackets.

The abbreviations which are customary in peptide chemistry are used todesignate bivalent radicals of natural α-amino acids. Provided it isknown, the configuration at the α-carbon atom is indicated by prefixingwith (L)- or (D)-. Glycyl which is bonded to the remainder of themolecule via the amino nitrogen and the carboxyl carbon is indicatedby - (cyclohexyl)Gly!- when it is substituted at the α-carbon atom by acyclohexyl radical and by - (phenyl)Gly!- when it is substituted at theα-carbon atom by a phenyl radical.

    ______________________________________    Abbreviations:    ______________________________________    abs.         absolute (indicates that the solvent                 is anhydrous)    anal. calc.  calculated value for elementary analysis                 (theoretical value)    anal. found  found value for elementary analysis                 (actual value)    atm          atmosphere (1 atm corresponds to 1.013 bar)    Boc          tert--butoxycarbonyl    BOP          benzotriazol-1-yloxytris(dimethylamino)                 phosphonium hexafluorophosphate    TLC          thin layer chromatography    DCC          dicyclohexylcarbodiimide    dimethoxyethane                 1,2-dimethoxyethane    DIPE         diisopropyl ether    DMF          dimethylformamide    DMPU         1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-                 pyrimidinone    EDC          N-ethyl-N'-(3-dimethylaminopropyl)-carbo-                 diimide hydrochloride    ether        diethyl ether    sat.         saturated    h            hour(s)    HBTU         O-benzotriazol-1-yl-N,N,N',N'-tetra-                 methyluronium hexafluorophosphate    HOBT         1-hydroxybenzotriazole    HV           high vacuum    min          minute(s)    MS           mass spectroscopy    sodium sulfate                 indicates disodium sulfate (Na.sub.2 SO.sub.4)    NMM          N-methylmorpholine    RT           room temperature    RE           rotary evaporator    saline       saturated solution of sodium chloride    THF          tetrahydrofuran    TBAF         tetrabutylammonium fluoride trihydrate    Z            benzyloxycarbonyl    ______________________________________

Example 1 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-(p-benzyloxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

95 mg (0.301 mmol) of TBAF are added, under a N₂ atmosphere, to asolution of 135 mg (0.151 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-benzyloxyphenyl)-2(R)-(p-benzyloxyphenyl)methyl!-hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in1.3 ml of DMF, and the mixture is stirred at RT for 16 h. The reactionmixture is poured onto water and this mixture is extracted with 4portions of ethyl acetate. The organic phases are washed with sat.NaHCO₃ solution, water and saline, dried with Na₂ SO₄ and evaporated.Digesting twice with DIPE yields the pure title compound: t_(Ret)(II)=18.5 min; FAB-MS (M+H)⁺ =782.

The starting material is prepared as follows:

1a) Z-(L)-Val-N-(2-methoxyethyl)amide

19.8 g (78.8 mmol) of Z-(L)-valine in 720 ml 0.25M NMM/CH₃ CN aretreated, under protective gas, with 7.5 ml (87.3 mmol) of2-methoxy-ethylamine (Fluka; Buchs/Switzerland). 32.3 g (85.2 mmol) ofHBTU are added to the thick, white suspension, and this mixture isthoroughly stirred at RT for 24 h. The reaction mixture is evaporatedunder high vacuum and the residue is taken up in ethyl acetate; thesolution is extracted with water, 2×10% citric acid solution, water,2×sat. NaHCO₃ solution and saline. The aqueous phases are extractedtwice more with ethyl acetate, and the organic phases are dried with Na₂SO₄ and evaporated. Crystallization from ethyl acetate/hexane 1:1 leadsto the title compound: TLC R_(f) (G)=0.6; t_(Ret) (II)=11.5 min.

1b) H-(L)-Val-N-(2-methoxyethyl)amide

Hydrogenating 22.8 g (74 mmol) of Z-(L)-Val-N-(2-methoxyethyl)amide in496 ml of methanol, at RT under low pressure and in the presence of 2.3g of 10% Pd/C, yields, after filtering off the catalyst, evaporating thefiltrate and column chromatography (SiO₂, methylene chloride using2.5→5→7.5→10% methanol), the pure title compound as an oil: TLC R_(f)(B)=0.3; FAB-MS (M+H)⁺ =175; ¹ H-NMR (360 MHz, CD₃ OD): 0.90 and 0.95(2d, J=7 Hz, (H₃ C)₂ C), 1.9 (m, HC-Me₂), 3.05 (d, J=6 Hz, HC.sub.α),3.32 (s, H₃ C--O), 3.37 (m, H₂ C), 3.44 (m, H₂ C).

1c)5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-benzyloxyphenyl)-2(R)-(p-benzyloxyphenyl)methyl!-hexanoyl-(L)-Val-N-(2-methyloxyethyl)amide

Under an N₂ atmosphere, 100 mg (0.135 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-benzyloxyphenyl)-2(R)-(p-benzyloxyphenyl)methyl!hexanoic acid preparation, see Example 1j)!and 26 mg (0.148 mmol) of H-(L)-Val-N-(2-methoxyethyl)amide aredissolved in 1.2 ml of 0.25M NM/CH₃ CN, and the solution is treated with56.3 mg (0.148 mmol) of HBTU. After 18 h at RT, the reaction mixture isevaporated and the residue is taken up in ethyl acetate; the solution isthoroughly washed with water, 2 portions of 10% citric acid solution,water, 2 portions of sat. NaHCO₃ solution and, finally, saline. Theinorganic phases are extracted two more times with ethyl acetate and theorganic phases are dried with Na₂ SO₄ and evaporated to give the titlecompound: t_(Ret) (II)=24.4 min; FAB-MS (M+H)⁺ =896.

1d) p-Benzyloxybenzyl iodide

A solution of 1.0 g (4.3 mmol) of 4-benzyloxybenzyl chloride (Fluka;Buchs/Switzerland) in 8 ml of acetone is stirred at RT with 3.13 g (20.9mmol) of sodium iodide. After 90 min, a gas chromatogram of the reactionmixture indicates that the reaction is complete; the reaction mixture istherefore poured onto ether, and this mixture is washed with 10% sodiumthiosulfate solution and saline. Drying the organic phase with Na₂ SO₄,and evaporating, yields the title compound: ¹ H-NMR (200 MHz, CDCl₃ :4.48 (s, 2H), 5.06 (s, 2H), 6.85-6.95 (m, 2H), 7.25-7.48 (m, 7H).

1e) (S)-N-Boc-(p-Benzyloxyphenylalaninol

37.1 g (100 mmol) of Boc-(L)-(p-benzyloxy)phenylalanine (Bachem;Bubendorf/Switzerland) in 116 ml of THF are treated, at from -5° C. to-10C, with 15.33 ml (110 mmol) of triethylamine, and a solution of 14.36ml (110 mmol) of isobutyl chloroformnate in 70 ml of THF is added tothis mixture. After stirring at RT for 0.5 h, the precipitate which hasformed is filtered off with suction. The filtered reaction mixture isadded dropwise to 7.57 g (200 mmol) of sodium borohydride and 44 ml ofH₂ O (approximately 10-15° C.), and this mixture is thoroughly stirredat RT for 3.5 h. The pH of the mixture is adjusted to 2 by adding 10%citric acid solution, and the mixture is partially evaporated on an RE.The residue is extracted with 3 portions of ethyl acetate, and theorganic phases are washed with 2×2N NaOH, saline, saturated NaHCO₃solution and saline, dried with Na₂ SO₄ and evaporated; the crudeproduct is digested in hexane to give the title compound: TLC R_(f)(C)=0.50; FAB-MS (M+H)⁺ =358.

1f) (S)-N-Boc-(p-Benzyloxyphenylalaninal)

4.76 g (37.5 mmol) of oxalyl chloride in 33.6 ml of methylene chlorideare treated dropwise, at -60° C. and under a N₂ atmosphere, with asolution of 3.5 ml (49 mmol) of DMSO in 60 ml of methylene chloride.After the mixture has been stirred for 15 min, 8.94 g (25 mmol) of(S)-N-Boc-(p-benzyloxyphenylalaninol) in 150 ml of methylene chlorideare added, and this mixture is subsequently stirred for about 25 min. 14ml (100 mmol) of triethylamine in 30 ml of methylene chloride are thenadded and the mixture is stirred for 30 min. 222 ml of a 20% of a KHSO₄solution and 187 ml of hexane are added, and the mixture is warmed to 0°C. The aqueous phase is separated off and extracted 2× with ethylacetate. The organic phases are washed with saturated NaHCO₃ solutionand saline, dried with Na₂ SO₄ and evaporated to give the titlecompound: TLC R_(f) (C)0.71; ¹ H-NMR (200 MHz, CDCl₃): 1.44 (s, 9H),3.06 (d, J=6 Hz, 2H), 4.39 (m, 1H), 5.03 (s +sb, H₂ C--O+HN), 6.86-6.98and 7.03-7.15 (2m, each 2H), 7.30-7.48 (m, 5H), 9.62 (s, 1H).

1g) 5(S)-1(S)-(Boc-Amino)-2-(p-benzyloxyphenyl)ethyl!dihydrofuran-2-(3H)-one (seeA. E. DeCamp et al., Tetrahedron Lett. 32, 1867 (1991))

6.0 g (91.8 mmol) of Zn/Cu (preparation: see R. D. Smith, H. E. Simmons,W. E. Parham, M. D. Bhavsar, Org. Synth., Coll. Vol 5, 855 (1973)) and9.69 ml of dimethylacetamide are added, under an N₂ atmosphere, to asolution of 7.7 ml (57.1 mmol) of ethyl 2-iodopropionate (Example 1k))in 100 ml of toluene, and this mixture is subsequently stirredvigorously at RT for 1 h and at 80° C. for 4 h (→Zn homoenolatesolution). In a second apparatus, a solution of 4.17 ml (14.2 mmol) oftetraisopropyl orthotitanite in 12 ml of toluene and 69 ml of methylenechloride is treated, under an N₂ atmosphere and while cooling slightly,with 4.41 ml (40.2 mmol) of TiCl₄ ; this mixture is stirred at RT for 15min (results in a yellow solution) and cooled down to -40° C., resultingin trichlorotitanium isopropoxide being obtained. The Zn homoenolatesolution is decanted off from the metallic solid and transferred bymeans of a cannula to the trichlorotitanium isopropoxide, which has beencooled down to -40° C., with the temperature being maintained at from-40 to -30° C. (deep-red solution). The solution is warmed to -25° C.for 5 min and then cooled down once again to -40° C. A solution of 9.7 g(27 mmol) of (S)-N-Boc-(p-benzyloxyphenyl)alaninal in 24.5 ml ofmethylene chloride is then added dropwise and the mixture issubsequently stirred at approximately -20° C. for 15 h and finally at 0°C. for 1 h. The reaction mixture is poured onto 0.4 kg of ice-water and0.5 l of ether, and this mixture is stirred vigorously for 10 min. Theaqueous phase is separated off and extracted with 2 portions of ether;the organic phases are washed with water, sat. sodium hydrogen carbonatesolution, water and saline, dried with sodium sulfate and evaporated(→crystalline ethyl5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)hexanoate).

The intermediate mentioned immediately above is heated in 220 ml oftoluene and 6.73 ml of acetic acid at 100° C. for 2.5 h. The cooledreaction mixture is treated with 0.5 l of water, and the aqueous phaseis separated off and extracted with 2 portions of ether; the org. phasesare washed with sat. sodium hydrogen carbonate solution, water andsaline, dried with sodium sulfate and evaporated. Crystallization of theresidue from ether/hexane yields the pure title compound: TLC R_(f)(E)=0.28; t_(Ret) (I)=23.5 min; ¹ H-NMR (200 MHz, CDCl₃): 1.40 (s, 9H),2.03-2.2 and 2.44-2.64 and 2.73-2.98 (3m, each 2H), 3.95 and 4.48 (2m,each 1H), 4.62 (d, J=9 Hz, 1H), 6.87-6.97 and 7.09-7.21 (2m, each 2H),7.27-7.48 (m, 5H).

1h) 5(S)- 1(S)-(Boc-Amino)-2-(p-benzyloxyphenyl)ethyl!-3(R)-(p-benzyloxyphenyl)-methyl!dihydrofuran-2-(3H)-one

2.47 g (6.0 mmol) of 5(S)-1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)ethyl!dihydrofuran-2-(3b)-onedissolved in 12 ml of THF and 1.2 ml of1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone are treated, at -70°C. and under a protective gas, with 11.73 ml of a 1 M solution oflithium bis(trimethylsilyl)amide in THF, and this mixture is stirred for15 min; it is then alkylated with 1.946 g (6.0 mmol) ofp-benzyloxybenzyl iodide (Example 1d)) in 3 ml of THF (60 min). Forhydrolysing, 2.23 ml of propionic acid and 2.23 ml of water are addedand the mixture is warmed to 0° C. The reaction mixture is poured onto30 ml of 10% citric acid solution, and this mixture is extracted twicewith ethyl acetate; the organic phases are washed twice with saturatedNaHCO₃ solution and, finally, with sa line. Drying the organic phaseswith Na₂ SO₄ and evaporating them, and column chromatography (SiO₂,hexane/ethyl acetate 4:1) of the residue, and subsequent crystallizationfrom ethyl acetate/hexane, affords the pure title compound: TLC R_(f)(D)=0.45; t_(Ret) (I)=19.9 min; FAB-MS (M+H)⁺ =608.

1i) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-(p-benzyloxyphenyl)methyl!hexanoic acid

2.7 g (4.43 mmol) of 5(S)-1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)ethyl!-3(R)-(p-benzyloxyphenyl)methyl!dihydrofuran-2-(3)-one in 59 ml ofdimethoxyethane and 31.8 ml of water are treated, while excluding air,with 14.8 ml of a 1 M lithium hydroxide solution. The mixture is thenstirred at RT for 3 h and partially evaporated. The residue is pouredonto a mixture of ice, 181 ml of sat. NH₄ Cl solution, 16.2 ml of 10%citric acid solution and 400 ml of ethyl acetate , and THF is addeduntil the precipitated solid dissolves. The aqueous phase is separatedoff and extracted with 2 portions of ethyl acetate, and the organicphases are washed with saline, dried with Na₂ SO₄, evaporated anddigested in hexane: TLC R_(f) (C)=0.07.

1j)5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-benzyloxy-phenyl)-2(R)-(p-benzyloxyphenyl)methyl!hexanoic acid

2.44 g (3.90 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-(p-benzyloxyphenyl)methyl!-hexanoic acid in 14 ml of DMF are stirred,under an N₂ atmosphere, together with 2.70 g (17.6 mmol) oftert-butyldimethylchlorosilane and 2.18 g (32 mmol) of imidazole at RTfor 18 h. The reaction mixture is poured onto ice-water, and thismixture is extracted with 3 portions of ethyl acetate; the organicphases are washed with 10% citric acid solution, H₂ O and saline, driedwith Na₂ SO₄ and evaporated. The resulting oil is taken up in 30 ml ofmethanol/THF/H₂ O 3:1:1, and this solution is treated with 3.2 g of K₂CO₃ and stirred at RT for 1 h. The reaction mixture is partiallyevaporated, and the aqueous residue is poured onto 10% citric acidsolution and ice, and this mixture is extracted 3× with ethyl acetate;the organic phases are washed twice with H₂ O and, finally, with saline,dried with Na₂ SO₄ and evaporated. Column chromatography (SiO₂,hexane/ethyl acetate 2:1→1:1) of the crude product affords the titlecompound: TLC R_(f) (C)=0.53; FAB-MS (M+H)⁺ =740.

1k) Ethyl 2-iodopropionate

A suspension of 170 ml of ethyl 2-bromopropionate (Fluka;Buchs/Switzerland) and 950 g of sodium iodide in 1.8 l of acetone isstirred at 60° C. for 20 h. The reaction mixture is filtered, and thefiltrate is partially evaporated, with the residue being poured ontoapproximately 2.5 l of ether; this mixture is washed with 1.0 l of 1%sodium thiosulfate solution and, finally, saline, dried with sodiumsulfate and evaporated. Distillation (83° C., 20 mbar) affords the puretitle compound: MS (M)⁺ =228; ¹ H-NMR (200 MHz, CDCl₃): 4.17 (q, 7 Hz,2H), 3.34 and 2.97 (2t, 7 Hz, 2×2H), 1.28 (t, 7 Hz, 3H).

Example 2 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-cyanophenyl)methyl!-hexanoyl-(L)-Val-N-(2-methoxyethlyl)amide

In analogy with Example 1), 2.73 g (3.85 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(p-cyanophenyl)methyl!-hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in 90.4ml of DMF are desilylated with 3.65 g (11.6 mmol) of TBAF, and workedup. Crystallization from methylene chloride/hexane results in the titlecompound: t_(Ret) (I)=14.0 min; FAB-MS (M+H)⁺ =595.

The starting material is prepared as follows:

2a) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(p-cyanophenyl)methyl!-hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

2.173 g (3.93 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(p-cyanophenyl)methyl!hexanoic acid preparation, see Example 2e)!, 839mg (4.07 mmol) of DCC and 596 mg (4.41 mmol) of HOBT are added, whileexcluding air, to the solution of 753.2 mg (4.32 mmol) ofH-(L)-Val-N-(2-methoxy-ethyl)amide (Example 1b) in 47 ml of THF. After24 h at RT, the reaction mixture is filtered and the filtrate isevaporated. The residue is partitioned between 3 portions of ethylacetate, 10% citric acid solution, sat. NaHCO₃ solution and saline.Drying the organic phases with Na₂ SO₄, evaporating them, and stirringup the residue in DIPE yields the title compound: t_(Ret) (II)=20.8 min.

2b) 5(S)- R(S)-(Boc-Amino)-2-phenylethyl!dihydrofuran-2-(3H)-one (see,also, A. E. DeCamp, A. T. Kawaguchi, R. P. Volante, and I. Shinkai,Tetrahedron Lett. 32, 1867 (1991)).8.03 g of Zn/Cu (preparation: R. D.Smith, H. E. Simmons, W. E. Parham, M. D. Bhavsar, Org. Synth., Coll.Vol 5, 855 (1973)) and 12.96 ml of dimethylacetamide are added, under aN₂ atmosphere, to a solution of 17.4 g of ethyl 2-iodopropionate(Example 1k)) in 130 ml of toluene, and the mixture is subsequentlystirred vigorously at RT for 1 h and at 80° C. for 4 h (→Zn homoenolatesolution). In a second apparatus (N₂ atmosphere), a solution of 5.58 ml(18.9 mmol) of tetraisopropyl orthotitanate in 16.4 ml of toluene and91.8 ml of methylene chloride is treated, while cooling slightly, with5.90 ml (53.8 mmol) of titanium tetrachloride, and this mixture isstirred at RT for 15 min (→yellow solution) and cooled down to -40° C.(→partial crystallization of the trichlorotitanium isopropoxide). Usinga cannula, the Zn homoenolate solution, which has been cooled down toRT, is decanted off from the metallic solid and added dropwise to thetrichlorotitanium isopropoxide, with the temperature being maintained atfrom -40° C. to -30° C. (→deep-red solution); the mixture is warmed to-25° C. for 5 min and then cooled down once again to →40° C. A solutionof 9.0 g of (S)-N-Boc-phenylalaninal (preparation: see D. J. Kempf, J.Org. Chem. 51, 3921 (1986)) in 32.8 ml of methylene chloride issubsequently added dropwise, and this mixture is stirred atapproximately -20° C. for 15 h and, finally, at 0° C. for 1 h. Thereaction mixture is poured onto 0.5 kg of ice-water and 0.5 l of ether,and this mixture is stirred vigorously for 10 min. The aqueous phase isseparated off and extracted with 2 portions of ether, the organic phasesare washed with 2 portions of water, saturated sodium hydrogen carbonatesolution and saline, dried with sodium sulfate and evaporated.Crystalline ethyl 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl hexanoate isobtained as an intermediate. This intermediate is heated at 80° C. for2.5 h in 295 ml of toluene and 9 ml of acetic acid. The reaction mixtureis treated with 0.5 l of water, and the aqueous phase is separated offand extracted with 2 portions of ether; the org. phases are washed withsaturated sodium hydrogen carbonate solution, water and saline, anddried with sodium sulfate. Partial evaporation of the organic phases,and treatment with hexane, affords the crystalline title compound,approximately 10% of which consists, according to analysis, of the (5R)epimer (TLC R_(f) (E)=0.08). Column chromatography (SiO₂, hexane/ethylacetate 2:1) yields the pure title compound: TLC R_(f) (E)=0.14; α!^(D)=17.7° (c=1; ethanol).

2c) 5(S)- 1(S)-(Boc-Amino)-2-phenyethyl!-3(R)-(p-cyano-phenyl)methyl!dihydrofuran-2-(3H)-one

In analogy with Example 1h), 1.5 g of 5(S)-1(S)-(Boc-amino)-2-phenylethyl!dihydrofuran-2-(3H)-one, dissolved in 32ml of THF, are deprotonated with 9.8 ml of a 1 M solution of lithiumbis(trimethylsilyl)amide in THF, and alkylated with 1.0 g of4-bromomethylbenzonitrile (Fluka; Buchs/Switzerland) dissolved in 3 mlof THF. Column chromatography (SiO₂, hexane/ethyl acetate 1:1) affordsthe pure title compound: TLC R_(f) (D)=0.33.

2d) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-cyanophenyl)methyl!hexanoic acid

In analogy with Example 1i), 0.50 g of 5(S)-1(S)-(Boc-amino)-2-phenylethyl!-3(R)-(p-cyanophenyl)methyl!dihydrofuran-2-(3H)-one in 19 ml ofdimethoxyethane and 10 ml of water is hydrolysed with 4.8 ml of a 1 Mlithium hydroxide solution to form the title compound: TLC R_(f)(B)=0.3.

2e) 5(5)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-pehyl-2(R)-(p-cyano-phenyl)methyl!hexanoic acid

In analogy with Example 1j), 0.62 g of5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-cyano-phenyl)methyl!hexanoic acid in 6.2 ml of DMF is silylated with0.98 g of tert-butyldimethylchlorosilane and 0.79 g of imidazole.Hydrolysis of the silyl ester function with 1.2 g of potassium carbonatein 31 ml of methanol/THF/water, 3:1:1, yields the title compound, afteracidifying with citric acid solution and extracting with ethyl acetate:TLC R_(f) (D)=0.29; FAB-MS (M+H)⁺ =553.

Example 3 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(o-fluorophenyl)methyl!-hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 1), 184.9 mg (0.263 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(o-fluorophenyl)methyl!-hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in 5 mlof DMF are desilylated with 249.3 mg (0.79 mmol) of TBAF, and worked up.Stirring-up with DIPE affords the title compound: t_(Ret) (II)=14.8 min;FAB-MS (M+H)⁺ =588.

The starting material is prepared as follows:

3a) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(o-fluorophenyl)methyl!-hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

168.9 mg (0.309 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(o-fluorophenyl)methyl!-hexanoic acid preparation, see Example 3d)!,77.1 mg (0.374 mmol) of DCC and 45.5 mg (0.337 mmol) of HOBT are added,under protective gas, to the solution of 59.3 mg (0.34 mmol) ofH-(L)-Val-N-(2-methoxyethyl)amide (Example 1b) in 3.5 ml of THF. After24 h at RT, the reaction mixture is filtered and the filtrate isevaporated. Partitioning the residue between 3 portions of ethylacetate, 10% citric acid solution, sat. NaHCO₃ solution and saline,drying the organic phases with Na₂ SO₄, and evaporating them, yields thetitle compound: t_(Ret) (II)=22.3 min.

3b) 5(S) 1(S)-(Boc-Amino)-2-phenylethyl!-3(R)-(o-fluorophenyl)methyl!dihydrofuran-2-(3H)-one

In analogy with Example 1h), 5.0 g (16.37 mmol) of 5(S)-1(S)-(Boc-amino)-2-phenylethyl!dihydrofuran-2-(3H)-one Example 2b)!dissolved in 75 ml of THF are deprotonated, at -75° C., with 32.7 ml ofa 1 M solution of lithium bis(trimethylsilyl)amide in THF, and alkylatedwith 2.1 ml (18.0 mmol) of o-fluorobenzyl bromide (Fluka;Buchs/Switzerland) at -75° C. initially (heating to a maximum of -60° C.over a period of 60 min). Column chromatography (SiO₂, hexane/ethylacetate, 3:1) affords the title compound: TLC R_(f) (D)=0.61.

3e) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(o-fluorophenyl)methyl!hexanoic acid

In analogy with Example 1i), 4.5 g (10.8 mmol) of 5(S)-l(S)-(Boc-amino)-2-phenylethyl!-3(R)-(o-fluorophenyl)methyl!dihydrofuran-2-(3H)-one in 170 ml ofdimethoxyethane are hydrolysed with 43.5 ml of a 1 M lithium hydroxidesolution. The evaporation residue of the reaction mixture is poured ontoa mixture of ice, 120 ml of sat. ammonium chloride solution and 240 mlof 10% citric acid solution, and this mixture is then extracted with 3portions of methylene chloride. The organic phases are washed with waterand saline, dried over Na₂ SO₄ and evaporated: t_(Ret) (II)=14.5 min.

3d) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(o-fluorophenyl)methyl!-hexanoyl acid

In analogy with Example 1j), 1.5 g (3.47 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(o-fluorophenyl)methyl!hexanoic acid in 15 ml DMF are silylated with 2.4g (16 mmol) of tert-butyldimethylchlorosilane and 1.95 g (28.5 mmol) ofimidazole. Hydrolysis of the silyl ester function with 2.8 g ofpotassium carbonate in 50 ml of methanol/THF/water, 4:1:1, yields thetitle compound after column chromatography (SiO₂, hexane/ethyl acetate,2:1): TLC R_(f) (D)=0.33; t_(Ret) (II)=20.7 min.

Example 4 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,4-difluorophenyl)-methylhexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 1), 197 mg (0.274 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,4-difluorophenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in 5ml of DMF are desilylated with 173 mg (0.548 mmol) of TBAF, and workedup. Precipitating with DIPE from a concentrated solution in methylenechloride yields the title compound: TLC R_(f) (A)=0.71; t_(Ret)(II)=14.9 min; FAB-MS (M+H)⁺ =606.

The starting material is prepared as follows:

4a) 5(S)-(Boc-Amino)-4(S) -(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,4-difluorophenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

68 mg (0.39 mmol) of H-(L)-Val-N-(2-methoxyethyl)amide (Example 1b),80.5 mg (0.39 mmol) of DCC and 57.5 mg (0.426 mmol) of HOBT are added,under an N₂ atmosphere, to 200 mg (0.354 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,4-difluorophenyl)methyl!hexanoic acid preparation, see Example 4d)!in 4.6 ml of THF. After 19 h at RT, the mixture is worked up, in analogywith Example 3a) to give the title compound: TLC R_(f) (D)=0.14; t_(Ret)(II)=21.7 min.

4b) 5(S) - 1(S)-(Boc-Amino)-2-phenylethyl!-3(R)-(2,4-difluorophenyl)methyl!-dihydrofuran-2-(3H)-one

In analogy with Example 1h), 5.0 g (16.37 mmol) of 5(S)-1(S)-(Boc-amino)-2-phenylethyl!dihydrofuran-2-(3H)-one Example 2b)!dissolved in 100 ml of THF are deprotonated, at -75° C., with 32.7 ml ofa 1 M solution of lithium bis(trimethylsilyl)amide in THF, and alkylatedwith 2.51 ml (19.6 mmol) of 2,4-difluorobenzyl bromide (Aldrich;Milwaukee/USA) at -75° C. initially (heating to a maximum of -60° C.over a period of 2 h). Column chromatography (SiO₂, hexane/ethylacetate, 2:1) affords the title compound: TLC R_(f) (D)=0.5; t_(Ret)(II)=17.2 min.

4c) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,4-difluorophenyl)melhy!-hexanoic acid

In analogy with Example 1i), 3.1 g (7.18 mmol) 5(S)-1(S)-(Boc-amino)-2-phenyl-ethyl!-3(R)-(2,4-difluorophenyl)methyl!dihydrofuran-2-(3H)-one in 77 ml ofdimethoxyethane and 19 ml of water are hydrolysed with 28.7 ml of a 1 Mlithium hydroxide solution (19 h at RT) to give the title compound:t_(Ret) (II)=14.7 min.

4d) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-2,4-difluorophenyl)methyl!hexanoic acid

In analogy with Example 1j), 3.2 g (7.12 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,4-difluorophenyl)methyl!hexanoic acid in 67 ml of DMF are silylatedwith 4.93 g (32.7 mmol) of tert-butyldimethylchlorosilane and 3.97 g(58.4 mmol) of imidazole. Hydrolysis of the silyl ester function with5.9 g of potassium carbonate in 77 ml of methanol, 20 ml of THF and 20ml of water yields the title compound after column chromatography (SiO₂,hexane/ethyl acetate, 2:1): TLC R_(f) (D)=0.22; t_(Ret) (II)=20.8 min.

Example 5 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-{p-(2-phenyl-ethyl)phenyl!methyl}-hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 1), 115 mg (0.146 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-{p-(2-phenylethyl)phenyl!-methyl}-hexanoyl-(L)-Val-N-(2-methoxyethyl)amidein 2.1 ml of DMF are desilylated with 92 mg (0.292 mmol) of TBAF, andextracted: TLC R_(f) (A)=0.58; t_(Ret) (II)=18.1 min.

The starting materials are prepared as follows:

5a) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-{p-(2-phenylethyl)phenyl!methyl}hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

Under an N₂ atmosphere, 100 mg (0.158 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-{p-(2-phenylethyl)phenyl!methyl}hexanoic acid (Example 5f)) and 30 mg(0.174 mmol) of H-(L)-Val-N-(2-methoxyethyl)amide (Example 1b) aredissolved in 1.52 ml of 0.25M NMM/CH₃ CN, and this solution is treatedwith 66 mg (0.174 mmol) of HBTU. After 18 h at RT, the reaction mixtureis poured onto water, and this mixture is extracted with 3 portions ofethyl acetate. The organic phases are washed with 10% citric acidsolution, water, sat NaHCO₃ solution, water and saline, dried with Na₂SO₄ and evaporated: t_(Ret) (II)=24.4 min.

5b) p-(2-Phenylethyl)benzyl alcohol

Hydrogenating 10 g (48 mmol) of 4-stilbenemethanol (Aldrich;Milwaukee/USA) in 100 ml of 1THF, in the presence of 0.5 g of 5% Pd/Cunder low pressure and at RT, filtering through ®Celite (filtering aidbased on kieselguhr; Johns-Manville Corp., obtainable from Fluka, Buchs,Switzerland) and evaporating the filtrate affords the title compound,approximately 15% of which, according to the ¹ H-NMR spectrum, consistsof p-(2-phenylethyl)toluene: TLC R_(f) (A)=0.62; ¹ H-NMR (200 MHz,CDCl₃): 2.92 (s, 4H), 4.68 (s, 2H), 7.15-7.35 (m, 9H).

5c) p-(2-Phenylethyl)benzyl bromide

3.14 ml (33.4 mmol) of phosphorus tribromide in 11 ml of toluene areadded dropwise, while cooling and under an N₂ atmosphere, to 8.36 g(85%; 33.4 mmol) of p-(2-phenylethyl)benzyl alcohol in 100 ml oftoluene. After 2 h at RT, the mixture is poured onto ice-water and theorganic phase is separated off; it is washed with sat. NaHCO₃ solution,water and saline. The aqueous phases are extracted 2× with ether, andthe combined organic phases are dried with Na₂ SO₄ and evaporated: TLCR_(f) (A)=0.77; ¹ H-NMR (200 MHz, CDCl₃): 2.92 (s, 4H), 4.50 (s, 2H),7.15-7.35 (m, 9H); additional signals of approximately 20%p-(2-phenylethyl)toluene.

5d) 5(S)- 1(S)-(Boc-Amino)-2-phenylethyl!-3(R)-{p-(2-phenylethyl)phenyl!methyl}-dihydrofuran-2-(3H)-one

A solution of 4.4 g (14.53 mmol) of 5(S)-1(S)-(Boc-amino)-2-phenylethyl!dihydrofuran-2-(3H)-one preparation, seeExample 2b)! in 21.4 ml of abs. THF and 2.4 ml of DMPU is treated, at-75° C. and under an N₂ atmosphere, with 28 ml of a 1 M solution oflithium bis(trimethylsilyl)amide in THF (Aldrich, Steinheim, FRG), andthe mixture is subsequently stirred at this temperature for 15 min. Asolution of 6.0 g (approximately 80%, 17.5 mmol) ofp-(2-phenylethyl)benzyl bromide in 5.4 ml of abs. THF is then addeddropwise, and this mixture is thoroughly stirred at -70° C. for 30 min.5.4 ml of propionic acid are then added at -75° C., followed by 5.4 mlof water. The mixture is warmed to 0° C. and diluted with 150 ml ofethyl acetate; this mixture is then washed with 80 ml of a 10% solutionof citric acid, with sat. sodium bicarbonate solution and with saline.The aqueous phases are reextracted 2× with ethyl acetate, and theorganic phases are dried over sodium sulfate and evaporated. Columnchromatography (SiO₂, hexane/ethyl acetate, 3:1) yields the pure titlecompound: TLC R_(f) (E)=0.27; t_(Ret) (II)=20.8 min; FAB-MS (M-Buten+H)⁺=444.

5e) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-{p-(2-phenylethyl)phenyl!-methyl}hexanoic acid

5.15 g (10.31 mmol) of 5(S)- 1(S)-(Boc-amino)-2-phenylethyl!-3(R)-{p-(2-phenylethyl)-phenyl!methyl}dihydrofuran-2-(3H)-one in 166 ml ofdimethoxyethane and 85 ml of water are hydrolysed, under protective gas,with 41 ml of a 1 M lithium hydroxide solution. After 3 h, thedimethoxyethane is evaporated off on an RE, and the residue is treatedwith an ice-cold mixture of 506 ml of sat. NH₄ Cl solution, 42 ml of 10%citric acid solution and 207 ml of methylene chloride. Methanol is addedto dissolve the product completely. The aqueous phase is separated offand extracted 2× with methylene chloride/methanol, 10:1. The organicphases are washed with saline, dried with Na₂ SO₄ and evaporated:t_(Ret) (II)=17.8 min.

5f) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R) -{p-(2-phenylethyl)phenyl!methyl}hexanoic acid

5.08 g (9.81 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-{p-(2-phenylethyl)phenyl!methyl}hexanoic acid in 22 ml of DMF aresilylated, under a protective gas, with 6.80 g (45.1 mmol) oftert-butyldimethylchlorosilane and 5.48 g (80.4 mmol) of imidazole at RTfor 20 h. The reaction mixture is poured onto 500 ml of ice-water, andthis mixture is extracted 3× with ethyl acetate. The organic phases arewashed with 10% citric acid solution, 2× water and saline, dried withNa₂ SO₄ and evaporated. The residue is dissolved in 119 ml of methanoland 46 ml of THF, and this solution is treated with 8.1 g of potassiumcarbonate and 46 ml of water, and then stirred at RT for 17 h. Thereaction mixture is subsequently poured onto ice-cold 10% citric acidsolution, and this mixture is extracted 3× with ethyl acetate. Theorganic phases are washed with 2 portions of water and saline, driedwith Na₂ SO₄ and evaporated. Column chromatography (SiO₂, hexane/ethylacetate 2:1→1:1→ethyl acetate) results in the pure title compound: TLCR_(f) (D)=0.22; t_(Ret) (II)=23.3 min.

Example 6 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-{p-(2,6-dichlorobenzylsulfonyl)phenyl!methyl}hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 1), 241 mg (0.27 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-{p-(2,6-dichlorobenzylsulfonyl)phenyl!methyl}hexanoyl-(L)-Val-N-(2-methoxyethyl)amideare deprotected with 170 mg (0.54 mmol) of TBAF in 3.6 ml of DMF over aperiod of 17 h. Stirring up in a little ethyl acetate, adding DIPE andfiltering off results in the pure title compound: TLC R_(f) (B)=0.67;t_(Ret) (II)=16.2 min; FAB-MS (M+H)⁺ =792.

The starting material is prepared as follows:

6a) 5(S)- 1(Boc-Amino)-2-phenylehtyl!-3(R)-{p-(2,6-dichlorobenzylsulfonyl)-phenyl!methyl}dihydrofuran-2-(3H)-one

In analogy with Example 5d), 5.0 g (16.34 mmol) of 5(S)-1(S)-(Boc-amino)-2-phenylethyl!dihydrofuran-2-(3H)-one, dissolved in 24ml of abs. THF and 2.7 ml of DMPU, are deprotonated, at -75° C., with32.7 ml of a 1 M solution of lithium bis(trimethylsilyl)amide in THF,and alkylated, at -75° C., with 9.67 g (24.5 mmol) ofp-(2,6-dichlorobenzylsulfonyl)benzyl bromide (Maybridge; Tintagel/UK) in50 ml of abs. THF. Protonation, at -75° C., with 6.1 ml (81.7 mmol) ofpropionic acid and 6.1 ml of water, extraction and column chromatography(SiO₂, hexane/ethyl acetate, 2:1) of the crude product, andcrystallization from DIPE, affords the title compound: TLC R_(f)(D)=0.30; t_(Ret) (II)=17.3 min.

6b) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-{p-(2,6-dichlorobenzylsulfonyl)-phenyl!methyl}hexanoic acid

In analogy with Example 5e), 6.7 g (10.83 mmol) of 5(S)-1(S)-(Boc-amino)-2-phenylethyl!-3(R)-{p-(2,6-dichlorobenzylsulfonyl)phenyl!methyl}dihydrofuran-2-(3H)-one in170 ml of dimethoxyethane are hydrolysed with 43.3 ml of a 1 M lithiumhydroxide solution (RT, 17 h). Partitioning between 3× methylenechloride, NH₄ Cl/citric acid solution and saline, and stirring the crudeproduct in ether, affords the title compound: t_(Ret) (II)=15.5 min.

6c) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-{p-(2,6-dichlorobenzylsulfonyl)-phenyl!methyl}hexanoic acid

In analogy with Example 5f), 5.0 g (7.85 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-{p-(2,6-dichlorobenzylsulfonyl)phenyl!methyl}hexanoic acid in 74 ml ofDMF are silylated with 5.4 g (36.1 mmol) oftert-butyldimethylchlorosilane and 4.4 g (64.4 mmol) of imidazole.Hydrolysis of the silyl ester function with 6.5 g of potassium carbonatein 85 ml of methanol, 22 ml of THF and 22 ml of water yields the titlecompound after column chromatography (SiO₂, hexane/ethyl acetate, 1:1)and stirring-up with DIPE: TLC R_(f) (C)=0.5; t_(Ret) (II)=21.0 min.

6d) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-{p-(2,6-dichlorobenzylsulfonyl)-phenyl!methyl}hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

200 mg (0.27 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-{p-(2,6-dichlorobenzylsulfonyl)phenyl!-methyl}hexanoic acid and 51.7 mg(0.297 mmol) of H-(L)-Val-N-(2-methoxyethyl)amide (Example 1b),dissolved in 2.6 ml of a 0.25 M solution of NMM in CH₃ CN, are reacted,at RT for 18 h under a nitrogen atmosphere, with 112.6 mg (0.297 mmol)of HBTU and subsequently worked up, in analogy with Example 5a), to givethe title compound: TLC t_(Ret) (D) =0.21; t_(Ret) (II)=21.9 min.

Example 7 5(S)-(Boc-Amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

1.11 g (1.35 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-benzyloxy-phenyl)-2(R)-(p-methoxy-phenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)-amide in 15ml DMF are desilylated, under an N₂ atmosphere, with 0.85 g (2.70 mmol)of TBAF. After 18 h at RT, the reaction mixture is poured onto water,and this mixture is extracted with methylene chloride. The organicphases are washed with sat. NaHCO₃ solution and saline, dried with Na₂SO₄ and evaporated. Stirring-up in DIPE yields the title compound: TLCR_(f) (B)=0.6; t_(Ret) (II)=16.6 min; FAB-MS (M+H)⁺ =706.

7a) 5(S)- 1(S)-(Boc-Amino)-2-(p-benzyloxyphenyl)ethyl!-3(R)-(p-methoxyphenyl)-methyl!dihydrofuran-2-(3H)-one

In analogy with Example 5d), 2.9 g (7.04 mmol) of 5(S)-1(S)-(Boc-amino)-2-(p-benzyloxy-phenyl)ethyl!dihydrofuran-2-(3H)-one(preparation, see Example 1g)!, dissolved in 10.3 ml of THF and 1.2 mlof DMPU, are deprotonated, at -70° C., with 14.1 ml of a 1 M solution oflithium bis(trimethylsilyl)amide in THF, and alkylated (at from -75° C.to -50° C.), with 2.6 g (10.57 mmol) of p-methoxybenzyl iodidepreparation, see Example 7e)! in 10 ml of THF. Protonation, at -75° C.,with 2.6 ml (35.2 mmol) of propionic acid and 2.6 ml of water,extraction and column chromatography (SiO₂, hexane/ethyl acetate, 2:1)affords the title compound: TLC R_(f) (D)=0.48; t_(Ret) (II)=18.8 min.

7b) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-(p-methoxyphenyl)-methyl!hexanoic acid

2.6 g (4.89 mmol) of 5(S)-1(S)-(Boc-amino)-2-(p-benzyloxy-phenyl)-ethyl!-3(R)-(p-methoxyphenyl)methyl!dihydrofuran-2-(3H)-one in 50 ml ofdimethoxyethane are hydrolysed, under an N₂ atmosphere, with 19.6 ml ofa 1 M lithium hydroxide solution in water. After 25 h at RT, thedimethoxyethane is evaporated off on a RE, and the residue is treatedwith an ice-cold mixture of 150 ml of sat. NH₄ Cl solution, 25 ml of 10%citric acid solution and methylene chloride. The aqueous phase isseparated off and extracted 2× with methylene chloride. The organicphases are washed with saline, dried with Na₂ SO₄ and evaporated to givethe title compound: TLC R_(f) (B)=0.28; t_(Ret) (II)=16.4 min.

7c)5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-benzyloxyphenyl)-2(R)-(p-methoxyphenyl)-methyl!hexanoic acid

2.5 g (4.54 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxy-phenyl)-2(R)-(p-methoxyphenyl)methyl!hexanoic acid in 42 ml of DMP are silylated,under a protective gas, with 3.15 g (20.9 mmol) oftert-butyldimethylchlorosilane and 2.53 g (37.3 mmol) of imidazole at RTfor 20 h. The reaction mixture is diluted with ethyl acetate, and thismixture is washed with sat. NaHCO₃ solution, water and saline. Theaqueous phases are extracted 2× with ethyl acetate, and the organicphases are dried with Na₂ SO₄ and evaporated. The residue is dissolvedin 50 ml of methanol and 13 ml of THF, and this solution is treated with3.8 g of potassium carbonate and 13 ml of water, and stirred at RT for 1h. Subsequently, the reaction mixture is partially evaporated and theresidue is diluted with ice-cold 10% citric acid solution; this mixtureis then extracted 3× with ethyl acetate. The organic phases are washedwith 2 portions of water and saline, dried with Na₂ SO₄ and evaporated.Column chromatography (SiO₂, hexane/ethyl acetate, 2:1) results in thepure title compound: TLC R_(f) (C)=0.13; t_(Ret) (II)=21.7 min. 7d)5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-benzyloxyphenyl)-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

960 mg (1.44 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-benzyloxy-phenyl)-2(R)-(p-methoxy-phenyl)methyl!hexanoic acid and 290 mg (1.66 mmol) ofH-(L)-Val-N-(2-methoxyethyl)amide (Example 1b) in 14.5 ml of 0.25 MNM/CH₃ CN are reacted, at RT for 20 h and under an N₂ atmosphere, with630 mg (1.66 mmol) of HBTU. The mixture is evaporated and the residue istaken up in ethyl acetate; the solution is washed in turn with water, 2×with 10% citric acid solution, once again with water, 2× with saturatedNaHCO₃ solution, water and saline. The aqueous phases are extractedtwice more with ethyl acetate, and the organic phases are dried with Na₂SO₄ and evaporated. Digesting the crude product in hexane results in thetitle compound: TLC R_(f) (B)=0.70; t_(Ret) (II)=22.5 min.

7e) p-Methoxybenzyl iodide

A solution of 1.7 ml (12.8 mmol) of 4-methoxybenzyl chloride (Fluka;Buchs/Switzerland) in 25 ml of acetone is stirred, at RT, together with9.4 g (62.6 mmol) of sodium iodide. A gas chromatogram of the reactionmixture, carried out after 90 min, indicates that the reaction iscomplete; the reaction mixture is therefore poured onto ether and thismixture is washed with 10% sodium thiosulfate solution and saline.Drying the organic phase with Na₂ SO₄, and evaporating it, affords thetitle compound: ¹ H-NMR (200 MHz, CD₃ OD: 3.78 (s, 3H), 4.54 (s, 2H),6.8-6.95 and 7.2-7.4 (2m, each 2H).

Example 8 5(S) -(Boc-Amino)-4(S)-hydroxy-6-(p-hydroxyphenyl)-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

Hydrogenating 500 mg (0.708 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide(Example 7) under low pressure in 33 ml of methanol in the presence of0.11 g of 10% Pd/C yields the title compound, after filtration,evaporation of the filtrate and digestion with DIPE: TLC R_(f) (B)=0.53;t_(Ret) (II)=12.2 min; FAB-MS (M+H)⁺ =616.

Example 9 5(S)-(Boc-Amino)-4(S)-hydroxy-6-(p-methoxyphenyl)-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

100 mg (0.162 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-hydroxy-phenyl)-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide(Example 8) in 3 ml of DMF/dioxane, 1:1, are treated, at 0° C. and underan N₂ atmosphere, with 105 mg (0.324 mmol) of Cs₂ CO₃ and 10.1 μl (0.162mmol) of methyl iodide, and the mixture is stirred at RT for 20 h. Forthe working-up, the reaction mixture is poured onto water, and thismixture is extracted with 3 portions of methylene chloride. The organicphases are washed with water and saline, dried with Na₂ SO₄ andevaporated. Stirring up in DIPE in an ultrasonication bath yields thetitle compound: TLC R_(f) (B)=0.62; t_(Ret) (II)=14.2 min; FA!B-MS(M+H)⁺ =630.

Example 10 5(S)-(Boc-Amino)-4(S)-hydroxy-6-(p-(isobutoxy)-phenyl)-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

100 mg (0.162 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-hydroxyphenyl)-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide(Example 8) in 3 ml of DMF/dioxane, 1:1, are treated, at 0° C. and underprotective gas, with 105 mg (0.324 mmol) of Cs₂ CO₃ and 18.7 μl (0.162mmol) of isobutyl iodide, and this mixture is stirred at 50° C. for 16h. Since HPLC indicates that starting material is still present, 5equivalents of isobutyl iodide and 10 equivalents of Cs₂ CO₃ are addedin portions. After each portion, the mixture is stirred at 50° C. for 1day until HPLC indicates that all the5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-hydroxyphenyl)-2(R)-(p-methoxyphenyl)methyl!-hexanoyl-(L)-Val-N-(2-methoxyethyl)amide hasreacted. Working up in analogy with Example 9 affords the titlecompound: TLC R_(f) (B)=0.76; t_(Ret) (II)=16.8 min; FAB-MS (M+H)⁺ =672.

Example 115S)-(Boc-Amino)-4(S)-hydroxy-6-(p-methoxyphenyl)-2(R)-(phenylmethyl)hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

2.07 g (2.90 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-methoxyphenyl)-2(R)-(phenylmethyl)hexanoyl-(L)-Val-N-(2-methoxyethyl)amidein 50 ml of DMF are desilylated, under an N₂ atmosphere, with 1.83 g(5.80 mmol) of TBAF. After 18 h, the reaction mixture is poured ontowater, and this mixture is extracted with 4 portions of ethyl acetate.The organic phases are washed with sat. NaHCO₃ solution, water andsaline, dried with Na₂ SO₄ and evaporated. Digesting twice with DIPEyields the title compound: t_(Ret) (II)=14.2 min; FAB-MS (M+H)⁺ =600.

The starting material is prepared as follows:

11a) 5(S)-1(S)-(Boc-Amino)-2-(p-methoxyphenyl)ethyl!dihydrofuran-2-(3H)-one

A suspension of 4.00 g (12.44 mmol) of 5(S)-1(S)-(Boc-amino)-2-(p-hydroxyphenyl)-ethyl!dihydrofuran-2-(3H)-one(Example 11f)) in 240 ml of DMF/dioxane, 1:1, is reacted, under an N₂atmosphere, with 8.1 g (24.88 mmol) of Cs₂ CO₃ and 0.77 ml (12.44 mmol)of methyl iodide. After 18 h, the reaction mixture is poured onto 190 mlof ice-water, and this mixture is extracted 3× with methylene chloride.The organic phases are washed with water and saline, dried with Na₂ SO₄and evaporated. Stirring with hexane in an ultrasonication bath affordsthe title compound: TLC R_(f) (C)=0.43; t_(Ret) (II)=13.5 min; FAB-MS(M+H)⁺ =336.

11b) 5(S)-1(S)-(Boc-Amino)-2-(p-methoxyphenyl)ethyl-3(R)-(phenylmethyl)-dihydrofuran-2-(3H)-one

In analogy with Example 5d), 4.17 g (12.44 mmol) of 5(S)-1(S)-(Boc-amino)-2-(p-methoxyphenyl)ethyl!dihydrofuran-2-(3H)-one,dissolved in 22.4 ml of THF and 2.5 ml of DMPU, are deprotonated, at-70° C., with 24 ml of a 1 M solution of lithiumbis(trimethylsilyl)amide in THF, and alkylated (-75° C., 1 h) with 1.5ml (12.44 mmol) of benzyl bromide. Protonation, at -75° C., with 4.6 mlof propionic acid and 4.6 ml of water, extraction and columnchromatography (SiO₂, methylene chloride/ether 25:1) yields the titlecompound: TLC R_(f) (C)=0.74; t_(Ret) (II)=16.6 min; FAB-MS (m++H)⁺=426.

11c)5(S)-(Boc-Amino)-4(S)-hydroxy-6-(p-methoxyphenyl)-2(R)-(phenylmethyl)-hexanoicacid

3.00 g (7.05 mmol) of 5(S)-1(S)-(Boc-amino)-2-(p-methoxy-phenyl)-ethyl!-3(R)-(phenylmethyl)dihydrofuran-2-(3H)-onein 112 ml of dimethoxyethane and 57 ml of water are hydrolysed, underprotective gas, with 28 ml of 1 M lithium hydroxide solution. After 20 hat RT, the reaction mixture is poured onto an ice-cold mixture of 340 mlof sat. NH₄ Cl solution, 28 ml of 10% citric acid solution and 140 ml ofmethylene chloride. Methanol is added in order to dissolve the productcompletely. The aqueous phase is separated off and extracted 2× withmethylene chloride. The organic phases are washed with saline, driedwith Na₂ SO₄ and evaporated, with the title compound being obtained:t_(Ret) (II)=14.0 min; FAB-MS (M+H)⁺ =444.

11d)5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-methoxyphenyl)-2(R)-(phenylmethyl)hexanoicacid

2.9 g (6.54 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-methoxyphenyl)-2(R)-(phenylmethyl)hexanoicacid in 7 ml of DMF are silylated, at RT for 20 h and under an N₂atmosphere, with 4.5 g (30 mmol) of tert-butyldimethylchlorosilane and3.65 g (53.6 mmol) of imidazole. The reaction mixture is poured onto 500ml of ice-water, and this mixture is extracted 3× with ethyl acetate.The organic phases are washed with 10% citric acid solution, 2× waterand saline, dried with Na₂ SO₄ and evaporated. Hydrolysis of the residuein 80 ml of methanol and 30 ml of THF with 5.4 g of potassium carbonateand 30 ml of water, working up after 3 h in analogy with Example 7c),and column chromatography (SiO₂, hexane/ethyl acetate, 2:1), affords thetitle compound: TLC R_(f) (D)=0.13; t_(Ret) (II)=20.3 min.

11e)5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-methoxyphenyl)-2(R)-(phenylmethyl)hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

1.56 g (2.8 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-methoxyphenyl)-2(R)-(phenylmethyl)hexanoicacid and 538 mg (3.09 mmol) of H-(L)-Val-N-(2-methoxyethyl)amide(Example 1b) in 27 ml of 0.25 M NMM/CH₃ CN are reacted, at RT for 20 hand under an N₂ atmosphere, with 1.17 g (3.09 mmol) of HBTU. Working upin analogy with Example 5a) results in the title compound: t_(Ret)(II)=21.1 min; FAB-MS (M+H)⁺ =714.

11 f) 5(S)-1(S)-(Boc-Amino)-2-(p-hydroxyphenyl)ethyl!dihydrofuran-2-(3H)-one

Hydrogenating 3.0 g (7.29 mmol) of 5(S)-1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)-ethyl!dihydrofuran-2-(3H)-onepreparation, see Example 1g)! in 100 ml of methanol with 0.6 g of 10%Pd/C yields the title compound after filtering off the catalyst andevaporating the filtrate: t_(Ret) (II)=10.6 min.

Example 12 5(S)-(Boc-Amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethoxy)amide

Under an argon atmosphere, 115.6 g (160.5 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide aredissolved in 650 ml of DMF, and this solution is treated with 101.3 g(321 mmol) of TBAF. After 20 h at RT, the reaction mixture is pouredonto 1 kg of ice and 500 ml of ethyl acetate, and the aqueous phase isseparated off and extracted a further 2× with 500 ml of ethyl acetate oneach occasion. The organic phases are washed with 2×500 ml of water, 500ml of sat. NaHCO₃ solution, 500 ml of water and 500 ml of saline. Dryingwith Na₂ SO₄, evaporation, stirring up in 2 l of ether/hexane, 1:1, andfiltering off, yields the title compound: TLC R_(f) (A)=0.35; t_(Ret)(II)=17.1 min; FAB-MS (M+H)⁺ =606; IR (KBr): inter alia, 3328s, 2922s,1685s, 1650s, 1622s, 1531s, 1512s, 1448m, 1390m, 1365m, 1246s, 1174s.

The starting material is prepared as follows:

12a) 5(S)- 1(S)-(Boc-Amino)-2-cyclohexylethyl!dihydrofuran-2-(3H)-one

A solution of 122.2 g (400 mmol) of 5(S)-1(S)-(Boc-amino)-2-phenylethyl!dihydrofuran-2-(3H)-one preparation, seeExample 2b)! in 1500 ml of methanol is hydrogenated, at RT and under lowpressure, in the presence of 4.0 g of Nishimura catalyst Rh(III)- andPt(IV)-oxide monohydrate, Degussa!. Filtering off the catalyst, andevaporating the filtrate, results in the title compound: TLC R_(f)(D)=0.54; FAB-MS (M+H)⁺ =312.

12b) 5(S)- 1(S)-(Boc-Amino)-2-cyclohexylethyl!-3(R)-(p-methoxyphenyl)methyl!-dihydrofuran-2-(3H)-one

880 ml of a 1 M solution of lithium bis(trimethylsilyl)amide in THF areadded dropwise, at -70° C., under an argon atmosphere and within thespace of 20 min, to 130 g (400 mmol) of 5(S)-1(S)-(Boc-amino)-2-cyclohexylethyl!dihydrofuran-2-(3H)-one which isdissolved in 1000 ml of abs. THF and 108 ml of DMPU. After 20 min, asolution of 110 g (443 mmol) of p-methoxybenzyl iodide preparation, seeExample 7e)! in 60 ml of abs. THF is added dropwise, and this mixture isthoroughly stirred at -75° C. for 2 h. The mixture is subsequentlyprotonated at -70° C. with 152 ml of propionic acid followed by 250 mlof water (temperature rises to -20° C.); 11 of ethyl acetate is thenadded and the reaction mixture is poured onto 2 l of 15% NaHCO₃solution. The aqueous phase is separated off and extracted with 1 l ofethyl acetate. The organic phases are washed 2× with sat. NaHCO₃solution, water and saline, dried with Na₂ SO₄ and evaporated. Columnchromatography (SiO₂, hexane/ethyl acetate, 9:1) and crystallizationfrom hexane yields the pure title compound: TLC R_(f) (E)=0.45; t_(Ret)(II)=18.6 min; FAB-MS (M+H)⁺ =432.

12c) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!-hexanoic acid

1000 ml of 1 M aqueous LiOH! solution are added, under a protective gas,to a solution of 103 g (239 mmol) of 5(S)-1(S)-(Boc-amino)-2-cyclohexylethyl!-3(R)-(p-methoxyphenyl)methylldihydrofuran-2-(3H)-one in 800 ml1,2-dimethoxyethane. After 3 h at RT, the reaction solution is pouredonto an ice-cold mixture of 1.5 l of sat. NH₄ Cl solution, 1 l of 10%citric acid solution and 2 l of ether. The aqueous phase is separatedoff and extracted 2× with 1 l of ether on each occasion. The organicphases are washed 4× with ice-water and finally with saline. Drying withsodium sulfate and evaporating yields the title compound from theorganic phases: t_(Ret) (II)=16.0 min; FAB-MS (M+H)⁺ =450.

12d)5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoic acid

133 g (1.95 mol) of imidazole and 164 g (1.09 mol) oftert-butyldimethylchlorosilane are added, under an argon atmosphere, toan ice-cold solution of 124 g (238 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoic acid in 800 ml of DMF. After 17 h atRT, the reaction mixture is poured onto 1.9 l of ice-water and extracted3× with 0.8 l of ethyl acetate on each occasion. The organic phases arewashed with water, sat. NaHCO₃ solution, water, 10% citric acidsolution, water and, finally, saline, dried with Na₂ SO₄ and evaporated.The residue is dissolved in 700 ml of methanol and 175 ml of THF, and175 g of K₂ CO₃ in 820 ml of water are added to this solution, which isthen stirred at RT for 1 h. The resulting emulsion is partiallyevaporated on an RE, and the residue is diluted with ice-water, and thismixture is acidified to pH 4 with 10% citric acid solution whilestirring vigorously. The mixture is extracted 3× with ethyl acetate, andthe organic phases are washed with water and saline, dried with Na₂ SO₄and evaporated. Column chromatography (SiO₂, hexane→hexane/ethyl acetate95:5→9:1→2:1→1:1) results in the title compound: TLC R_(f) (E)=0.15;t_(Ret) (II)=22.7 min.

12e)5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

33.2 g (190 mmol) of H-(L)-Val-N-(2-methoxyethyl)amide (Example 1b) in100 ml of DMF are added to a solution of 97.6 g (173.1 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoic acid in 600 ml of DMF, and the mixtureis cooled down to 10° C. 31.1 ml (93% pure, 190 mmol) of diethylcyanophosphonate (Aldrich, Milwaukee/USA) and 60.4 ml (432 mmol) oftriethylamine are then added. After 1 h at RT, the reaction mixture ispoured onto 1.5 l of ice-water, and this mixture is extracted 3× with0.5 l of ethyl acetate on each occasion. The ethyl acetate phases arewashed 2× with water, 10% citric acid solution, water, sat. NaHCO₃solution, water and saline, dried with Na₂ SO₄ and evaporated. Stirringup in 2 l of hexane at 50° C., cooling down to 5° C. and filtering offyields the pure title compound: TLC R_(f) (A)=0.7; TLC R_(f) (J)=0.2;t_(Ret) (II)=23.8 min; FAB-MS (M+H)⁺ =720.

Example 13 5(S)-{(1-Ethoxycarbonylpiperidin-4-yl)caronyl!amino}-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

An ice-cooled solution of 250 mg (0.461 mmol) of5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide(hydrochloride salt) in 3.5 ml of THF is treated, under an N₂atmosphere, with 212 μl (1.15 mmol) of triethylamine and a solution of101 mg (0.461 mmol) of (1-ethoxycarbonylpiperidin-4-yl)carbonyl chloride(see Example 13b), and this mixture is warmed to RT. After 2 h, thereaction mixture is poured onto water, and this mixture is extracted 3×with ethyl acetate. The organic phases are washed with water, sat.NaHCO₃ solution and saline, dried with Na₂ SO₄ and evaporated; theresidue is digested in DIPE to give the title compound: TLC R_(f)(B)=0.39; t_(Ret) (I)=14.4 min; FAB-MS (M+H)⁺ =689.

The starting material is prepared as follows:

13a) 5(S)-Amino-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide(hydrochloride salt)

43.8 g (72.3 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy)-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide(Example 12) are treated, while excluding moisture and while coolingwith ice, with 250 ml of 3.8 M HCl/dioxane, and this mixture is stirredfor 2 h. The reaction mixture is subsequently evaporated on a RE, andthe residue is taken up in 600 ml of dioxane, and this solution islyophilized. Stirring up the lyophilisate in 1 l of ether, filteringoff, and stirring up once again in 0.7 l of ethyl acetate and filteringoff, results in the title compound: t_(Ret) (I))=10.1 min; FAB-MS (M+H)⁺=506; anal: calc. C 60.94%, H 8.96%, N 7.61%, Cl 6.42%, H₂ O 1.76%;found C 60.7%, H 9.0%, N 7.7%, Cl 6.8%, H₂ O 1.76%. The second filtrate(ethyl acetate) is evaporated and the residue is taken up in ethylacetate; this solution is washed with sat. NaHCO₃ solution, water andsaline, dried with Na₂ SO₄ and evaporated. Column chromatography (SiO₂,ethyl acetate) of the residue affords 5(S)-1(S)-amino-2-cyclohexylethyl!-3(R)-(p-methoxyphenyl)methyl!dihydrofuran-2-(3H)-one: t_(Ret) (II)=11.3 min;FAB-MS (M+H)⁺ =332; IR (CH₂ Cl₂): inter alia 3390wb, 2930s, 2855m,1763s, 1612m, 1515s, 1245s, 1180s, 1037m.

13b) 4-Chlorocarbonyl-1-ethoxycarbonylpiperidine

A solution of 578.2 g of 4-carboxy-1-ethoxycarbonylpiperidine in 1200 mlof toluene is treated firstly with 1.0 g of N,N-dimethylformnamide andthen, at from 68 to 70° C. and within the space of 2 hours, with 369.0 gof thionyl chloride. The mixture is subsequently stirred at 70° C. for afurther 30 min, after which the toluene is distilled off in vacuo andthe residue is then degassed at RT for approximately 30 min under HV.This results in the title compound in the form of a weakly yellow oil IR(Film): 2960, 2870, 1790, 1695, 1470, 1435, 1300, 1230, 1130, 960, 765cm⁻¹ !. The product distils without decomposition at a m.p. of 96-98° C.(0.08-0.09 Torr).

13c) 4-Carboxy-1-ethoxycarbonylpiperidine

4-Carboxy-1-ethoxycarbonylpiperidine is prepared frompiperidine-4-carboxylic acid (Aldrich, Steinheim, FRG), for example byreacting piperidine-4-carboxylic acid with ethyl chloroformate inaqueous sodium hydroxide solution for 2 h at from 0 to 5° C. The titlecompound is extracted from the aqueous phase by shaking with toluene.The toluene phase containing the dissolved title compound is dried overNa₂ SO₄ and directly subjected to further use.

Example 14

The following compounds are prepared in analogy with one of the examplesgiven above or below:

I) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)(p-fluoro-p-methoxyphenyl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

II) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-(phenyl-2(R)-(p-fluoro-o-methoxyphenyl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

III) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-(phenyl-2(R)-(o-fluoro-p-methoxyphenyl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

IV)5(S)-(Boc-Amino)-4(S)-hydroxy-6-(p-methoxyphenyl-2(R)-(cyclohexylmethyl)-hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

80 mg (0.132 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-methoxyphenyl)-2(R)-(cyclohexen-1-yl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide(Example 14 V)) in 4 ml of ethanol/ethyl acetate, 3:1, are hydrogenatedin the presence of 40 mg of 5% Pd/C and under standard pressure.Filtering off the catalyst, washing the residue with methylenechloride/methanol and evaporating the filtrate yields a relatively largequantity of crystalline crude product. This is dissolved in methylenechloride/methanol, treated with silica gel and dried. Loading the powderonto a silica gel column and eluting with methylene chloride/ethylacetate/ethanol, 30:20:1, affords the title compound: TLC R_(f)(P)=0.28; t_(Ret) (II)=15.9 min; FAB-MS (M+H)⁺ =606.

V) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-(4-methoxyphenyl)-2(R)-cyclohexen-1-yl-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

Under a protective gas, 344 mg (0.479 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-methoxyphenyl)-2(R)-(cyclohexen-1-yl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide aredissolved in 9.9 ml of DMF, and this solution is treated with 302 mg(0.958 mmol) of TBAF. After 15 h at RT, the reaction mixture is pouredonto 160 ml of water, and this mixture is extracted with 3 portions ofethyl acetate. The organic phases are washed 2× with sat. NaHCO₃solution and saline, dried with Na₂ SO₄ and evaporated. Digestion withDIPE yields the title compound: TLC R_(f) (O)=0.56; TLC R_(f) (P)=0.28;t_(Ret) (II)=15.4 min; FAB-MS (M+H)⁺ =604.

The starting material is prepared as follows:

14 Va) Cyclohexen-1-ylmethanol

Under protective gas, a solution of 8.0 g (55.3 mmol) of1-cyclohexenecarbonyl chloride (Pfaltz & Bauer, Waterbury/USA) in 168 mlof ether is cooled down to -20° C. and treated with 2.35 g (62 mmol) oflithium aluminium hydride. After the mixture has been stirred at -16° C.for 1 h, 256 ml of ethyl acetate are added dropwise (exothermic),followed by 76 ml of a 2N solution of NaOH. The mixture is stirred at RTfor 30 min, 160 g of Na₂ SO₄ are added, and this mixture is thenfiltered. Na₂ SO₄ is added once again to the filtrate, which is thenfiltered. Evaporating the filtrate under mild conditions (20 mbar, 35°C.) affords the title compound: ¹ H-NMR (200 MHz, CDCl₃): 1.60 (m, 5H),2.00 (m, 2 H₂ C^(allyl).), 3.97 (s, H₂ C--OH), 5.66 (m, HC^(olefin)).

14 Vb) Cyclohexen-1-yl-methylbromide

A solution of 6.2 g (55.3 mmol) of cyclohexen-1-ylmethanol in 800 ml ofmethylene chloride is treated, at 0° C., with 27.5 g (83 mmol) oftetrabromomethane and 21.7 g (83 mmol) of triphenylphosphine. After 35min the mixture is evaporated on a RE under mild conditions. The residueis washed with 5 portions of pentane of 40 ml each. The combined pentanephases yield the title compound, after evaporation and kugelrohrdistillation (140-160° C., ≈20 mbar): ¹ H-NMR (200 MHz, CDCl₃): 1.6 (m,2 H₂ C), 2.1 (m, 2 H₂ C^(allyl).), 3.93 (s, H₂ C--Br), 5.88 (m,HC^(olefin)); ¹³ C-NMR (CDCl₃): 22.3, 22.9, 25.9 26.8 (4 CH₂), 40.4 (CH₂--Br), 128.6, 135.1(2 C^(olefin)).

14 Vc) 5(S)- 1(S)-(Boc-Amino)-2-(p-methoxyphenyl)ethyl!-3(R)-(cyclohexen-1-yl)-methyl!dihydrofuran-2-(3H)-one

A solution of 6.36 g (18.9 mmol) of 5(S)-1(S)-(Boc-amino)-2-(p-methoxyphenyl)ethyl!-dihydrofuran-2-(3H)-one(preparation, see Example 11a) in 34 ml of abs. THF and 3.8 ml of DMPUis treated, at -75° C. and under an N₂ atmosphere, with 36.5 ml of a 1 Msolution of lithium bis(trimethylsilyl)amide in THF (Aldrich). After 15min, a solution of 3.3 g (18.9 mmol) of cyclohexen-1-ylmethyl bromide ina little abs. THF is added dropwise, and this mixture is then stirredthoroughly at -70° C. for 1 h. 7 ml of propionic acid, and then 7 ml ofwater, are subsequently added at -75° C. The reaction mixture is warmedto 0° C. and poured onto 190 ml of ethyl acetate and 100 ml of 10%citric acid solution, and this mixture is then stirred for 5 min; theorganic phase is separated off and washed with sat. sodium bicarbonatesolution and saline. The aqueous phases are reextracted 2× with ethylacetate, and the organic phases are dried over sodium sulfate andevaporated. Column chromatography (SiO₂, hexane/ethyl acetate, 4:1→3:1)affords the pure title compound: TLC t_(f) (D)=0.54; t_(Ret) (II)=18.7min; FAB-MS (M-buten+H)⁺ =430.

14 Vd) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-methoxyphenyl)-2(R)-cyclohexen1-yl)-methyl!hexanoic acid

1.25 g (2.91 mmol) of 5(S)-1(S)-(Boc-amino)-2-(p-methoxyphenyl)ethyl!-3(R)-(cyclohexen-1-yl)methyl!dihydrofuran-2-(3H)-one in 43.4 ml ofdimethoxyethane and 22.1 ml of water are hydrolysed, under a protectivegas, with 10.8 ml of a 1 M lithium hydroxide solution. After 15 h, thereaction mixture is poured onto an ice-cold mixture of 140 ml of sat.NH₄ Cl solution, 12 ml of 10% citric acid solution and 58 ml ofmethylene chloride. The aqueous phase is separated off and extracted 2×with methylene chloride. The organic phases are washed with saline,dried with Na₂ SO₄ and evaporated: t_(Ret) (II)=15.6 min; FAB-MS(M-buten+H)⁺ =448.

14 Ve) 5(S)-(Boc-Amino)-4(S)-tert-butyldimethylsilyloxy)-6-(p-methoxyphenyl)-2(R)-(cyclohexen-1-yl)-methyl!hexanoic acid

Under a protective gas, 1.19 g (2.66 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy)-6-(p-methoxy-phenyl)-2(R)-(cyclohexen-1-yl)methyl!hexanoic acid are dissolved in 2.9 ml of DMF,and this solution is treated with 1.84 g (12.2 mmol) oftert-butyldimethylchlorosilane and 1.48 g (21.8 mmol) of imidazole.After 16 h at RT, the reaction mixture is poured onto 200 ml ofice-water, and this mixture is extracted 3× with ethyl acetate. Theorganic phases are washed with 10% citric acid solution, 2× water andsaline, dried with Na₂ SO₄ and evaporated. The residue is taken up in 32ml of methanol and 12 ml of THF, and this solution is treated with asolution of 2.2 g of potassium carbonate in 12 ml of water, and themixture is stirred at RT for 3 h. The reaction mixture is subsequentlypartially evaporated on a RE, and the residue is poured onto ice-cold10% citric acid solution, and this mixture is extracted 3× with ethylacetate. Washing the organic phases with 2 portions of water and saline,drying with Na₂ SO₄, and evaporating, affords the title compound: TLCR_(f) (D)=0.37; t_(Ret) (II)=22.8 min. 14 Vf)5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-methoxyphenyl)-2(R)-(cyclohexen-1-yl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

Under an N₂ atmosphere, 300 mg (0.613 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-methoxyphenyl)-2(R)-(cyclohexen-1-yl)methyl!hexanoic acid and 117 mg (0.674 mmol) ofH-(L)-Val-N-(2-methoxyethyl)amide (Example 1b)) are dissolved in 6,0 mlof 0.25 M NMM/CH₃ CN and 255.5 mg (0.674 mmol) of HBTU are added to thissolution. After 17 h at RT, the reaction mixture is evaporated under HVand the residue is taken up in ethyl acetate; this solution is washedwith water, 2×10% citric acid solution, 2×sat. NaHCO₃ solution andsaline. The aqueous phases are extracted a further 2× with ethylacetate, and the combined organic phases are dried with Na₂ SO₄ to givethe title compound: t_(Ret) (II)=23.3 min.

Example 15 5(S)-(Boc-Amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(4-benzyloxy-phenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 1, 0.35 g (0.44 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(4-benzyloxy-phenyl)-methyl!-hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in3 ml DMF is reacted with 0.278 g (0.88 mmol) of TBAF trihydrate to givethe title compound. Working up, stirring up with diethyl ether, andfiltering, yields the pure title compound. TLC R_(f) (B)=0.52; t_(Ret)(II)=18.06 min; FAB-MS (M+H⁺)=682.

15a) 3(R)- (4-Benzyloxyphenyl)methyl!-5(S)-1(S)-(Boc-amino)-2-cyclohexylethyl!-dihydrofuran-2-one

In analogy with Example 5d), 5.2 g (16.7 mmol) of 5(S)-1(S)-(Boc-amino)-2-cyclohexylethyl!-dihydrofuran-2-one (preparation, seeExample 12a)!, dissolved in 50 ml of THF, are deprotonated, at -70° C.,with 33.4 ml of a 1 M solution of lithium bis(trimethylsilyl)amide inTHF, and alkylated, at -75° C. for 1 h, with 5.2 g (16.07 mmol) of4-benzyloxybenzyl iodide preparation, see Example 1d)! in 15 ml of THF.Treating, at -75° C., with 6.2 ml (83.02 mmol) of propionic acid andwater, and further working up, affords the title compound after columnchromatography (SiO₂, hexane/ethyl acetate: 4/1). TLC R_(f)(hexane/ethyl acetate: 4/1)=0.27; t_(Ret) (II)=20.41 min.

15b) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(4-benzyloxyphenyl)methyl!-hexanoic acid

2.4 g (4.728 mmol) of 3(R)- (4-benzyloxyphenyl)methyl!-5(S)-1(S)-(Boc-amino)-2-cyclohexylethyl!dihydrofuran-2-one in 10 ml ofdimethoxyethane are hydrolysed, under a protective gas, with 9.45 ml ofa 1M solution of lithium hydroxide. After 17 h at RT, the reactionmixture is treated with an ice-cold mixture of 324 ml of sat. NH₄ Clsolution, 27 ml of 10% citric acid solution and 134 ml of methylenechloride. Methanol is added in order to dissolve the product completely.The aqueous phase is separated off and extracted 2× with methylenechloride. The organic phases are washed with saline, dried with Na₂ SO₄and evaporated. The crude product is purified by column chromatography(SiO₂, eluent C), with the title compound being obtained. TLC R_(f)(C)=0.35; t_(Ret) (II)=17.88 min. FAB-MS (M+H⁺)=526.

15c)5(S)-(Boc-Amino)-4(S)-tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(4-bezyloxyphenyl)methyl!hexanoic acid

In analogy with Example 5f), 28.8 g (54.8 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(4-benzyloxyphenyl)methyl!hexanoic acid in 288 ml of DMF are convertedinto the title compound using 35.8 g (237.6 mmol) oftert-butyldimethylchlorosilane and 30 g (440 mmol) of imidazole. Thetitle compound is purified by column chromatography (SiO₂, hexane/ethylacetate: 4/1 to 1/1); TLC R_(f) (E)=0.34; t_(Ret) (gradient from 75 to100% (a) in (b) over a period of 20 min)=25.06 min; FAB-MS (M+H⁺)=526.

15d)5(S)-(Boc-Amino)-4(S)-(tert-butyldimeyhylsilyloxy)-6-cyclohexyl-2(R)-(4-benzyloxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 12e, a solution of 3 g (18.7 mmol) ofH-(L)-Val-N-(2-methoxyethyl)amide and 10 g (15.6 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(4-benzyloxy-phenyl)methyl!hexanoic acid in 50 ml of DMF is cooled downto 5° C. in an ice bath and treated with 2.9 ml (17.2 ml) of diethylcyanophosphonate and, after that, with 5.5 ml of triethylamine. Afterhaving been stirred at RT, the mixture is poured onto water, and thismixture is extracted 3 times with ethyl acetate. The combined organicphases are washed with water, saturated sodium bicarbonate solution(twice) and saline, and are concentrated after having been dried oversodium sulfate under reduced pressure. The title compound is purified bycolumn chromatography (SiO₂,C); TLC R_(f) (A)=0.56; t_(Ret) (B)=24.82min FAB-MS (M+H⁺)=796.

Example 16 5(S)-(Boc-amino)-4(S)-(hydroxy)-6-cyclohexyl-2(R)-(4-hydroxyphenyl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 1, 0.547 g (0.775 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(4-hydroxy-phenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in 5ml of DMF is reacted with 0.488 g (1.549 mmol) of TBAF trihydrate togive the title compound. The pure title compound is obtained afterworking up and after stirring up with diethyl ether and filtering. TLCR_(f) (B)=0.37; t_(Ret) (II)=14.44 min; FAB-MS (M+H⁺)=592.

The starting compound is obtained in the following manner:

16a)5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(4-hydroxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide 0.64 g(0.804 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-4-(benzyloxy)phenylmethyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in 20ml of methanol is hydrogenated in the presence of 0.32 g of 10% Pd/C.The title compound, which is obtained after filtering off the catalystand evaporating the filtrate, is subjected to further reaction withoutany additional purification; TLC R_(f) (C)=0.18; t_(Ret) (II)=21.81 min;FAB-MS (M+H⁺)=706.

Example 17 5(S)-(Boc-Amino)-4(S)-(hydroxy)-6-cyclohexyl-2(R)-(4-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 1, 0.6 g (0.833 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-4-methoxyphenylmethyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in 5 mlof DMF is reacted with 0.526 g (1.67 mmol) of TBAF trihydrate to givethe title compound. After working up, the pure title compound isobtained after stirring up with diethyl ether and filtering. TLC R_(f)(A) =0.45; t_(Ret) (II)=16.14 min; FAB-MS (M+H⁺)=606.

The starting compound is prepared in the following manner:

17a)5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(4-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A solution of 0.75 g (1.06 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(4-hydroxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in 25ml of dioxane is treated with 1.384 g (4.25 mmol) of caesium carbonateand, after 1 h, with 2.07 ml (21.24 mmol) of methyl iodide. Afterstirring at RT for 16 h, the solid is filtered off and washed with ethylacetate. The filtrate is washed, in succession, with water, saturatedaqueous sodium bicarbonate solution and saline. After drying over sodiumsulfate, and evaporating under reduced pressure, the resulting residueis stirred up with hexane and filtered off, with the title compoundbeing obtained. TLC R_(f) (J)=0.6; t_(Ret) (II)=23.65 min; FAB-MS(M+H⁺)=720.

Example 185(S)-(2,2,2-Trifluoroethoxycarbonylamino)-4(S)-(hydroxy)-6-cyclohexyl-2(R)-(4-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

400 mg (0.791 mmol) of 5(S)-amino-4(S)-(hydroxy)-6-cyclohexyl-2-(R)-4-methoxyphenylmethyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in 5 mlDMF are treated, at 0° C. and in succession, with 0.276 ml (1.97 mmol)of triethylamine and 0.193 g (1.186 mmol) of trifluoroethylchloroformate (U.S. Pat. No. 3,852,464). After having been stirred for10 min, the reaction mixture is poured onto water, and this mixture isextracted 3 times with ethyl acetate. The combined extracts are washed,in succession, with aqueous, saturated sodium bicarbonate solution andsaline, and, after having been dried over sodium sulfate, areconcentrated under reduced pressure. The residue is crystallized fromethyl acetate/diethyl ether, with the title compound being obtained. TLCR_(f) (B)=0.78; t_(Ret) (II)=15.36 min; FAB-MS (M+H⁺)=632.

The starting compound is prepared in the following manner:

18a) 5(S)-Amino-4(S)-(hydroxy)-6-cyclohexyl-2(R)-(4-methoxyphenyl)methyl!-hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

2.27 g (3.747 mmol) of5(S)-(Boc-amino)-4(S)-(hydroxy)-6-cyclohexyl-2(R)-(4-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide(Example 17) in 20 ml of methylene chloride are treated with 20 ml oftrifluoroacetic acid at 0° C. After having been stirred for 2 h at RT,the reaction mixture is evaporated and partitioned between saturatedaqueous sodium bicarbonate solution and ethyl acetate. The organic phaseis washed once again with saturated aqueous sodium bicarbonate solutionand saline, and evaporated to dryness. The residue is digested withether and subsequently chromatographed (SiO₂, methylenechloride/methanol: 9/1 to 1/1), with the title compound being obtained.TLC R_(f) (B)=0.43; t_(Ret) (II)=10.23 min; FAB-MS (M+H⁺)=506.

Example 195(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(phenylmethyl)-hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 1, 0.82 g (1.19 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-N-(2-methoxyethyl)amidein 12 ml of DMF is reacted with 0.756 g (2.38 mnol) of TBAF trihydrateto give the title compound. After working up, the pure title compound isobtained after stirring up with diethyl ether and filtering. TLC R_(f)(A)=0.37; t_(Ret) (II)=14.58 min; FAB-MS (M+H⁺)=570.

The starting compound is prepared in the following manner:

19a) 5(S)- 1(S)(Boc-Amino)-2-phenylethyl!dihydrofuran-2-(3H)-one (seeEx. 2c))

(see, also, A. E. DeCamp, A. T. Kawaguchi, R. P. Volante, and I.Shinkai, Tetrahedron Lett. 32, 1867 (1991)). 173 g of Zn/Cu(preparation: see R. D. Smith, H. E. Simmons, W. E. Parham, M. D.Bhavsar, Org. Synth., Coll. Vol 5, 855 (1973)) and 280 ml ofdimethylacetamide are added, under an N₂ atmosphere, to a solution of375 g (1.65 mol) of ethyl 2-iodopropionate (Example 1k)) in 1700 ml oftoluene and this mixture is subsequently stirred vigorously at RT for 1h and at 80° C. for 4 h (→Zn-homoenolate solution). In a secondapparatus (N₂ atmosphere), a solution of 122 ml (0.40 mol) oftetraisopropyl orthotitanate in 350 ml of toluene and 1900 ml ofmethylene chloride is treated, with slight cooling, at an internaltemperature of from 15 to 25° C., with 127 ml (1.14 mol) of titaniumtetrachloride, and this mixture is stirred at RT for 15 min (→yellowsolution) and cooled down to -40° C. (→partial crystallization of thetrichlorotitanium isopropoxide). The Zn-homoenolate solution, which hasbeen cooled down to RT, is filtered, under an argon atmosphere, througha G3 glass frit and added dropwise to the trichlorotitaniumisopropoxide, with the temperature being maintained at from -30° C. to-25° C. (→deep-red solution), after which the mixture is stirred at -25°C. for 5 min and then cooled down to -40° C. A solution of 233 g (0.85mol) of (S)-N-Boc-phenylalaninal (preparation: see D. J. Kempf, J. Org.Chem. 51, 3921 (1986), then crystallization from hexane (0° C.,approximately 18 h), washing with cold hexane, and drying) in 1500 ml ofmethylene chloride is subsequently added dropwise, and the mixture isthen stirred at from -22 to -18° C. for 15 h and, finally, at 0° C. for1 h. The reaction mixture is taken up in 10 l of ice-water and 12 l oftert-butyl methyl ether, and this mixture is stirred vigorously for 7-10min. The aqueous phase is separated off; it is extracted 2× with 10 l ofether; the organic phases are washed with 8 l of water, 8 l of sat.sodium hydrocarbon carbonate solution, 8 l of water and 5 l of saline;they are dried with sodium sulfate and evaporated (→crystalline ethyl5(S)-(Boc-amino)-4(S)-hydroxy-6-phenylhexanoate).

The above intermediate is heated, in 6500 ml of toluene and 230 ml ofacetic acid and under an argon atmosphere, at 100° C. for 2.5 h. When ithas cooled down, the reaction mixture is poured, with stirring, onto 6 lof ice-water, and the aqueous phase is separated off and extracted 2×with 2000 ml of toluene; the org. phases are washed with 5 l of sat.sodium hydrogen carbonate solution, 5 l of 40% sodium hydrogen sulfitesolution, 4 l of water and 4 l of saline, and dried with sodium sulfate.Evaporating the org. phases down to a residue of approximately 300 g,and treating the latter with 800 ml of hexane (thorough stirring forseveral hours) affords crystalline lactone, which HPLC indicatescontains approximately 10% of the (5R) epimer (TLC R_(f) (E)=0.08;t_(Ret) (II)=18.8 min). This material is employed in the next stage. Thepure title compound can be obtained following column chromatography(SiO₂, hexane/ethyl acetate, 2:1): TLC R_(f) (E)=0.14; t_(Ret) (II)=19.2min; a!^(D) =17.7° (c=1; ethanol).

19b) 5(S)-1(S)-(Boc-Amino)-2-phenylethyl!-3(R)-phenylmethyldihydrofuran-2-(3H)-one

(see, also, A. K. Ohosh, S. P. McKee, and W. J. Thompson, J. Org. Chem.56, 6500 (1991)). Under an N₂ atmosphere, a solution of 1943 g (6.32mol) of 5(S)- 1(S)-(Boc-amino)-2-phenylethyl!dihydrofuran-2-(3H)-one in12.0 l of THF and 1.9 l of1,3-dim-ethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone is cooled down to-75° C. and treated, at an internal temperature of below -70° C., with14000 ml of a 1 M solution of lithium bis(trimethylsilyl)amide in THF(Aldrich), and this mixture is subsequently stirred at -75° C. for 20min. 835 ml (7.00 mol) of benzyl bromide are added dropwise to it overthe space of 1 h, during which time the internal temperature is notallowed to exceed -70° C., and the mixture is then thoroughly stirred at-75° C. for 30 min. 2320 ml of propionic acid (90 min) and then 2320 mlof water (1 h) are subsequently added to the clear solution, with thetemperature being allowed to rise to -10° C. The reaction mixture ispoured onto 30 l of ethyl acetate and 35 l of 10% citric acid solution,and the aqueous phase is separated off and reextracted 2× with 10 l ofethyl acetate. The organic phases are washed with 3×12 l of sat. sodiumbicarbonate solution, 20 l of saline and 2×20 l of water, and thenconcentrated. The oily residue is taken up in 10 l of toluene, and thismixture is evaporated down to a residue volume of approximately 5 l.Filtering the evaporation residue through 4 kg of Merck silica gel(0.063-0.200 mm), washing with toluene and crystallizing the crudeproduct from hexane (4 l of hexane/kg of crude product) affords thetitle compound: TLC R_(f) (D)=0.54; FAB-MS (M+H)⁺ =414.

19c) 5(S)-(Boc-Amino)-4(S)-hydro-6-phenyl-2(R)-phenylmethylhexanoic acid

A solution of 17.6 g of 5(S)-1(S)-(Boc-amino)-2-phenylethyl!-3(R)-phenylmethyldihydrofuran-2-(3H)onein 710 ml of ethylene glycol dimethyl ether and 352 ml of water istreated dropwise, at 20° C. and within the space of 10 min, with 176 mlof a 1 M lithium hydroxide solution. After that, the reaction mixture isstirred at RT for 1.5 h, and the solvent is then evaporated off. Theresidue is poured onto 1 l of cold 10% citric acid, and this acidicsolution is extracted three times with 800 ml of ethyl acetate on eachoccasion. The combined extracts are washed first with 800 ml of waterand then with 800 ml of saline. After the organic solution has beendried over sodium sulfate, the solvent is distilled off. The crude titlecompound is employed in the next stage without any further purification.FAB-MS (M+H)⁺ =414.

19d)5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-phenylmethylhexanoicacid

A solution of 6.35 g of5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-phenylmethylhexanoic acid in90 ml of DMF is treated, while being stirred, with 8 g of imidazole and10 g of t-butyldimethylchlorosilane. After having been stirred at RT for18 h, the yellow, clear solution is poured onto ice-water, and thismixture is extracted three times with 250 ml of ethyl acetate on eachoccasion. The combined extracts are washed, in succession, three timeswith 10% citric acid, once with water, three times with aqueous,saturated sodium bicarbonate solution, once with water and, finally,with saline. After drying over sodium sulfate, the solvent is evaporatedand the resulting tert-butyl dimethylsilyl ether (13.5 g) is dissolvedin 53 ml of THF and treated with 53 ml of acetic acid and 20 ml ofwater. After having been stirred at RT for 3 h, the mixture is pouredonto water, and this mixture is extracted three times with ether. Thecollected ether extracts are washed twice with water and once withsaline and dried over sodium sulfate. After concentrating, the crudeproduct is purified by column chromatography (SiO₂, hexane/ethylacetate: 3.5/1.5), and the title compound is obtained. TLC R_(f)(D)=0.37; FAB-MS (M+H)⁺ =528.

19e)5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(phenylmethyl)hexanoyl-(L)-Val-N-(2-methoxymethyl)amide

A solution of 1.25 g (2 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(phenylmethyl)hexanoicacid, 0.98 g (2.21 mmol) of BOP, 0.3 g (2.21 mmol) of HOBT and 0.55 ml(4.98 mmol) of N-methylmorpholine in 15 ml of DMF is treated, afterhaving been stirred at RT for 30 min, with 0.208 ml (2.42 mmol) of(L)-Val-N-(2-methoxyethyl)amide. After having been stirred at RT for 5.5h , the mixture is poured onto 300 ml of water, and this mixture isextracted 3 times with ethyl acetate. The combined organic phases arewashed with water, saturated sodium bicarbonate solution (twice) andsaline, and, after drying over sodium sulfate, are concentrated underreduced pressure. The title compound is purified by columnchromatography (SiO₂,D to A); TLC R_(f) (C)=0.23.

Example 205(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(phenyl-methyl)-hexanoyl-(L)-(cyclohexyl)Gly!-N-(2-methoxyethyl)amide

In analogy with Example 1, 0.96 g (1.33 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(phenylmethyl)hexanoyl-(L)-(cyclohexyl)Gly-N-(2-methoxyethyl)amidein 33 ml of DMF is reacted with 0.836 g (2.66 mmol) of TBAF trihydrateto give the title compound. The pure title compound is obtained afterworking up and column chromatography (SiO₂, D to A). TLC R_(f) (A)=0.5;t_(Ret) (II)=15.92 min; FAB-MS (M+H⁺)=610.

The starting compound is prepared in the following manner:

20a) N-Boc-(L)-(Cyclohexyl)glycine

2.51 g (10 mmol) of Boc-(L)-phenylglycine (Fluka, Buchs, Switzerland)are hydrogenated, at RT for 1 h under standard pressure, in 50 ml ofmethanol and in the presence of 250 mg of Nishimura catalyst. Thecatalyst is then filtered off and washed with methanol. The filtrate isevaporated and the resulting title product is employed in the next stagewithout further purification. TLC R_(f) (A)=0.41.

20b) Boc-(L)- (Cyclohexyl)Gly!-N-(2-methoxyethyl)amide

A solution of 0.515 g (2 mmol) of N-Boc-(L)-(cyclohexyl)glycine in 10 mlof methylene chloride is treated successively, after having been cooleddown to 0° C., with 0.413 g (2 mmol) of DCC and 0.297 g (2.2 mmol) ofHOBT. After 20 min, the mixture is treated over the space of 15 min witha solution of 0.172 ml (2 mmol) of 2-methoxyethylamine (Aldrich, Buchs,Switzerland) in 8 ml of methylene chloride. After the mixture has beenthoroughly stirred at RT for 19.5 h, the solid is filtered off. Thefiltrate is washed in succession with water and saline and dried oversodium sulfate. After concentrating under reduced pressure, the crudeproduct is purified by column chromatography (SiO₂, eluent J), with thetitle compound being obtained. TLC R_(f) (A)=0.56.

20c) H-(L)- (Cyclohexyl)Gly!-N-(2-methoxyethyl)amide

0.52 g (1.65 mmol) of Boc-(L)- (cyclohexyl)Gly!-N-(2-methoxyethyl)amideis stirred for 2 h in 8.7 ml of formic acid. After that, the mixture isevaporated on a rotary evaporator, and the remaining formic acid isremoved in vacuo. The residue is taken up in aqueous, saturated sodiumbicarbonate solution, and this mixture is extracted 4 times withmethylene chloride. The combined organic extracts are washed with waterand saline, dried over sodium sulfate and concentrated. The crude titlecompound is purified by column chromatography (SiO₂, eluent B). TLCR_(f) (A)=0.6.

20d)5(S)-(Bo-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(phenylmethyl)hexanoyl-(L)-(cyclohexyl)Gly!-N-(2-methoxyethyl)amide

A solution of 0.817 g (1.55 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(phenylmethyl)!hexanoicacid (Example 19e)), 0.365 g (1.7 mmol) of H-(L)-(cyclohexyl)Gly!-N-(2-methoxyethyl)amide, 0.645 g (1.7 mmol) of HBTU and0.4 ml (3.72 mmol) of N-methylmorpholine in 15 ml of acetonitrile isstirred at RT for 16 h. The reaction mixture is then concentrated andthe residue is taken up in ethyl acetate. After this solution has beenwashed with water, 10% citric acid, water, saturated aqueous sodiumbicarbonate solution and saline, it is dried over sodium sulfate. Afterconcentrating, the crude product is purified by column chromatography(SiO₂, C), with the title compound being obtained. TLC R_(f) (A)=0.53.

Example 215(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(phenylmethyl)hexanoyl-(L)-(phenyl)Gly!-N-(2-methoxyethyl)amide

In analogy with Example 1, 1.15 g (1.6 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(phenylmethyl)hexanoyl-(L)-(phenyl)Gly!-N-(2-methoxyethyl)amide in 37 ml of DMF are reacted with1.01 g (3.2 mmol) of TBAF trihydrate to give the title compound. Afterworking up, the pure title compound is obtained after columnchromatography (SiO₂, D to A). TLC R_(f) (A)=0.47; t_(Ret) (II)=15.15min; FAB-MS (M+H⁺)=604.

The starting compound is prepared in the following manner:

21a) Boc-(L)-(Phenyl)Gly-N-(2-methoxyethyl)amide

In analogy with Example 20b), a solution of 0.503 g (2 mmol) ofN-Boc-(L)-(phenyl)glycine in 10 ml of methylene chloride is treated insuccession, after having been cooled down to 0° C., with 0.413 g (2mmol) of DCC and 0.297 g (2.2 mmol) of HOBT. After 20 min, the mixtureis treated for 15 ml with a solution of 0.172 ml (2 mmol) of2-methoxyethylamine in 8 ml of methylene chloride. After thoroughlystirring at RT, and working up, the crude product is purified by beingstirred up in ether. TLC R_(f) (A)=0.5.

21b) H-(L)- (Phenyl)Gly!-N-(2-methoxyethyl)amide

In analogy with Example 20c), 0.61 g (1.98 mmol) of Boc-(L)-(phenyl)Gly!-N-(2-methoxyethyl)amid is stirred in 10.4 ml of formic acidfor 2 h. The title compound is obtained after working up and is subjected to further use without any additional purification. TLC R_(f)(B)=0.3.

21c)5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(phenylmethyl)hexanoyl-(L)-(phenyl)Gly!-N-(2-methoxyethyl)amide In analogy with Example 20d), asolution of 0.921 g (1.75 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(phenylmnethyl)hexanoicacid, 0.4 g (1.92 mmol) of H-(L)- (phenyl)Gly!-N-(2-methoxyethyl)amide,0.728 g (1.92 mmol) of HBTU and 17.4 ml (4.2 mmol) of a 0.25M solutionof N-methylmorpholine in acetonitrile is stiffed at RT for 22 h. Theworking-up, and the subsequent column chromatography (SiO₂, ethylacetatehexane: 1/1 to 3/1) give the title compound. TLC R_(f) (A)=0.63.

Example 22 5(S) -1-Methyl-4-piperdinyloxycarbonyl)amino!-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A solution of 346 mg (3 mmol) of 1-methyl-4-piperidinol (Fluka, Buchs,Switzerland) in 2 ml of THF is injected into a solution of 217 mg (0.73mmol) of triphosgene in 20 ml of THF. The resulting suspension is cooledin an ice bath and then treated with 1.16 ml (8.3 mmol) oftriethylamine, and the resulting mixture is subsequently stirred at RTfor 30 min. This suspension is added to a slurry of 500 mg (0.92 mmol)of 5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in 20ml of THF, and this mixture is stirred for 2 h under an argonatmosphere. The reaction mixture is poured onto ice water, and thismixture is extracted 2× with ethyl acetate. The organic extracts arewashed, in succession, with water, sat. sodium bicarbonate solution,water and saline, and evaporated. The title compound is obtained afterdigesting the crude product with ether, filtering off the insolubleconstituents with suction, and washing the residue with ether. TLC R_(f)(K)=0.60; t_(ret) (I)=10.8 min; FAB MS (M+H)⁺ =647.

The starting material is prepared as follows:

22a) 5(S)-Amino-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!-hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A solution of 5 g (8.25 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide fromExample 12 in 40 ml of 4N hydrochloric acid is stirred in dioxane for 2h in an ice bath. The reaction mixture is subsequently evaporated invacuo and the residue is lyophilized from dioxane, with the titlecompound being obtained. TLC R_(f) (B)=0.18; t_(ret) (I)=11.3 min; FABMS (M+H)⁺ =506.

Example 235(S)-(3(S)-Tetrahydrofuryloxycarbonyl-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A slurry of 1.0 g (1.84 mmol) of5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide fromExample 22a) in 30 ml of THF is treated, at -5° C., with 1.28 ml oftriethylamine and subsequently with 694 mg (4.61 mmol) of3(S)-tetrahydrofuryloxycarbonyl chloride (see J. Chromatography 506, 598(1990)) and this mixture is stirred at RT for 1 h under an argonatmosphere. The reaction mixture is poured onto ice-water, and thismixture is extracted 3× with ethyl acetate. The organic extracts arewashed successively with water, sat. sodium bicarbonate solution, waterand saline, and evaporated. The title compound is obtained afterdigesting the crude product with ethyl acetate, filtering off theinsoluble constituents with suction, and washing the residue with ethylacetate and ether. TLC R_(f) (B)=0.74; t_(ret) (I)=14.0 min; FAB MS(M+H)⁺ =620.

Example 245(S)-(2(R,S)-Tetrahydropyranylmethoxycarbonylamino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 23, the title compound is obtained as a mixtureof 2 epimers, which cannot be resolved by HPLC, by proceeding from 1.0 g(1.84 mmol) of 5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!-hexanoyl-(L)-Val-N-(2-methoxyethyl)amide fromExample 22a), 660 mg (3.68 mmol) of rac.tetrahydropyranylmethoxycarbonyl chloride (see Carbohydrate Res. 4(4),343 (1967)) and 0.909 ml (6.45 mmol ) of triethylamine. TLC R_(f)(B)=0.69; t_(ret) (I)=15.5 min; FAB MS (M+H)⁺ =648.

Example 25 5(S)-5(S)-2-Oxopyrrolidinylmethoxycarbonylamino)-4(S)-hydroxy-6-cyclohexyl-2-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 22, the title compound is obtained, afterchromatographic purification on silica gel using the eluent system K, byproceeding from 542 mg (1.0 mmol) of 5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!-hexanoyl-(L)-Val-N-(2methoxyethyl)amide fromExample 22a), 345 mg (3 mmol) of 5-(S)-hydroxymethyl-2-pyrrolidone(=(L)-pyroglutaminol--Fluka, Buchs, Switzerland), 297 mg (1 mmol) oftriphosgene and 1.25 ml (9 mmol) of triethylamine. TLC R_(f) (K)=0.50;t_(ret) (I)=12.6 min; FAB MS (M+H)⁺ =647.

Example 265(S)-(2-Methoxyethoxycarbonylamino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 23, the title compound is obtained by proceedingfrom 1.0 g (1.84 mmol of 5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!-hexanoyl-(L)-Val-N-(2-methoxyethyl)amide fromExample 22a), 511 mg (3.70 mmol) of 2-methoxyethoxycarbonyl chloride and0.909 ml (6.45 mmol) of triethylamine. TLC R_(f) (B)=0.63; t_(ret)(I)=13.9 min; FAB MS (M+H)⁺ =608.

The starting material is prepared as follows:

26a) 2-Methoxyethoxycarbonyl chloride (=2-methoxyethyl chloroformate)

13.3 ml (168 mmol) of 2-methoxyethanol (Fluka, Buchs, Switzerland) areadded dropwise, at from 0 to 5° C. and under a nitrogen atmosphere, to100 ml (202 mmol) of a 20% solution of phosgene in toluene, and thismixture is thoroughly stirred at 0° C. for 90 min and at RT for 18 h.The reaction mixture is extracted with water, and the organic phase isfiltered through wadding and evaporated: IR (CH₂ Cl₂): inter alia 3055w,2995w, 2935w, 2895w, 2825w, 1775s, 1167s, 1127s; ¹ -NMR (200 MHz,CDCl₃): 3.38 (s, 3H) 3.64 and 4.44 (2t, J=5 Hz, each 2H).

Example 275(S)-((L)-Thiazolidin-4-ylcarbonylamino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A solution of 1.0 g (1.84 mmol) of5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxy-phenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide fromExample 22a) in 12 ml of DMF is treated, at RT, in succession, with 270mg (2.02 mmol) of (L)-thiazolidine-4-carboxylic acid (=(L)-thiaproline;Sigma, Buchs, Switzerland), 0.33 ml (2.02 mmol) of diethylcyanophosphonate and 0.91 ml (6.52 mmol) of triethylamine, and theresulting suspension is stirred under an argon atmosphere for 1 h. Thesuspension is diluted with 40 ml of ethyl acetate and filtered. Theresidue is dissolved in a 9:1 mixture of methylene chloride andmethanol, and this mixture is then evaporated to dryness. The titlecompound is obtained as a white solid after digesting the residue withethyl acetate. TLC R_(f) (B)=0.72; t_(ret) (I)=10.5 min; FAB MS (M+H)⁺=621.

Example 285(S)-(4-Oxo-4H-1-benzopyran-2-ylcarbonylamino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A solution of 1.0 g (1.84 mmol) of5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxy-phenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide fromExample 22a) in 18 ml of DMF is treated, at RT, and in succession, with470 mg (2.40 mmol) of 4-oxo-4H-1-benzopyran-2-carboxylic acid (Aldrich,Steinheim, FRG), 0.59 ml (3.90 mmol) of diethyl cyanophosphonate and0.90 ml (6.45 mmol) of triethylamine, and the mixture is stirred for 5 hunder an argon atmosphere. For the working-up, the reaction mixture ispoured onto ice-water, and this mixture is extracted 2× with ethylacetate. The organic extracts are washed, in succession, with water,sat. sodium bicarbonate, water and saline, and then evaporated todryness. The title compound is obtained as a white solid afterchromatographic purification on silica gel using methylenechloride/methanol (98:2) and digesting with diethyl ether. TLC R_(f)(B)=0.63; t_(ret) (I)=15.4 min; FAB MS (M+H)⁺ =678.

Example 295(S)-(Indolyl-2-carbonylamino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 28, the title compound is obtained as a whitesolid, after digesting with diethyl ether, by proceeding from 1.0 g(1.84 mmol) of 5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide fromExample 22a), 331 mg (2.03 mmol) of indole-2-carboxylic acid (Fluka,Buchs, Switzerland), 0.331 ml (2.03 mmol) of diethyl cyanophosphonateand 0.90 ml (6.45 mmol) of triethylamine. TLC R_(f) (B)=0.75; t_(ret)(I)=14.4 min; FAB MS (M+H)⁺ =651.

Example 305(S)-(Methoxycarbonyl-(L)-Val-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxy-phenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 28, the title compound is obtained as a whitesolid, after digesting with diethyl ether, by proceeding from 1.0 g(1.84 mmol) of 5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide fromExample 22a), 462 mg (2.63 mmol) of methoxycarbonyl-(L)-valine, 0.43 ml(2.83 mmol) of diethyl cyanophosphonate and 1.34 ml (9.61 mmol) oftriethylamine. TLC R_(f) (B)=0.61; t_(ret) (I)=14.2 min; FAB MS (M+H)⁺=663.

The starting material is prepared as follows:

30a) N-(Methoxycarbonyl)-(L)-valine

5.67 g (60 mmol) of methyl chloroformate (Fluka, Buchs, Switzerland) areadded to 7.0 g (60 mmol) of L-valine in 100 ml of 2N NaOH and 30 ml ofdioxane (→exothermic reaction), and this mixture is subsequently stirredat RT for 18 h. The reaction mixture is extracted with methylenechloride, and the aqueous phase is acidified with 27 ml of 4N HCl andonce again extracted with methylene chloride. Drying and evaporating thelatter methylene chloride phase affords the title compound: t_(Ret)(I)=7.2 min; ¹ H-NMR (200 MHz, CD₃ OD): 0.96 (t, J=7 Hz, 6H), 2.16 (m,1H), 3.67 (s, 3H), 4.06 (m, 1H), 7.07 (d, J=8 Hz, HN_(partially)exchanged).

Example 31 5(S)-(N-((L)-Thiazolidin-4-ylcarbonyl)-(L)-Val!-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 28, the title compound is obtained as a whitesolid, after digesting with diethyl ether, by proceeding from 0.60 g(1.11 mmol) of 5(S)-amino-4(S)-hydroxy-6-cyclo-hexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxy-ethyl)amide fromExample 22a), 311 mg (1.33 mmol) of N-(L)-thiazolidin-4-ylcarbonyl!-(L)-valine (=(L)-thiaprolyl-(L)-valine),0.25 ml (1.63 mmol) of diethyl cyanophosphonate and 0.55 ml (3.91 mmol)of triethylamine. TLC R_(f) (K)=0.54; t_(ret) (I)=11.0 min; FAB MS(M+H)⁺ =720.

31a) H-(L)-Thiaprolyl-(L)-valine

In analogy with Example 28, (L)-thiaprolyl-(L)-valine benzyl ester isobtained by proceeding from 3.99 g (10.5 mmol) of (L)-valine benzylester 4-toluenesulfonate (Fluka, Buchs, Switzerland), 1.33 g (10.0 mmol)of (L)-thiazolidine-4-carboxylic acid (=(L)-thiaproline; Sigma, Buchs,Switzerland), 1.8 ml (11.0 mmol) of diethyl cyanophosphonate and 5.6 ml(40.0 mmol) of triethylamine. A solution of 1.37 g of this crude productin 15 ml of methanol is treated with 8.5 ml of a 1N sodium hydroxidesolution, and this mixture is stirred at RT for 2 h. The reactionsolution is evaporated down to half its volume in vacuo, and washed withethyl acetate. The aqueous phase is acidified with 1N hydrochloric acid,saturated with sodium chloride and extracted 4× with ethyl acetate. Thetitle compound is obtained after evaporating the organic extracts anddigesting the residue with ether. TLC R_(f) (K)=0.54; t_(ret) (III)=12.2min; FAB MS (M+H)⁺ =233.

Example 32 5(S)-(Benzyloxycarbonyl)-(L)-4-trans-hydroxyprolyl!amino)-4-(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 28, the title compound is obtained as a whitesolid, after chromatographic purification on silica gel using system Kand digesting with diethyl ether, by proceeding from 0.84 g (1.55 mmol)of 5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide fromExample 22a, 412 mg (1.55 mmol) oftrans-benzyloxycarbonyl-(L)-4-hydroxyproline (Bachem, Bubendorf,Switzerland), 0.26 ml (1.63 mmol) of diethyl cyanophosphonate and 0.5 ml(3.6 mmol) of triethylamine. TLC R_(f) (K)=0.50; t_(ret) (I)=13.8 min;FAB MS (M+H)⁺ =753.

Example 33 5(S)-((L)-trans-4-Hydroxyprolyl!amino)-4-(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A solution of 700 mg (0.93 mmol) of 5(S)-(benzyloxycarbonyl-(L)-4-trans-hydroxyprolyl!amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide fromExample 32 in 90 ml of methanol is hydrogenated, at RT for 2.5 h, in thepresence of 140 mg of 10% palladium on charcoal under 1 atm hydrogenpressure. The catalyst is filtered off, the filtrate is evaporated todryness, and the title compound is obtained as a white solid afterdigesting with diethyl ether. TLC R_(f) (K)=0.18; t_(ret) (I)=9.9 min;FAB MS (M+H)⁺ =619.

Example 345(S)-(2-Amino-4-thiazolylacetylamino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 28, the title compound is obtained as a whitesolid, after digesting with diethyl ether, by proceeding from 0.60 g(1.11 mmol) of 5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide fromExample 22a), 211 mg (1.33 mmol) of 2-amino-4-thiazoleacetic acid(Aldrich, Steinheim, FRG), 0.25 ml (1.63 mmol) of diethylcyanophosphonate and 0.55 ml (3.91 mmol) of triethylamine. TLC R_(f)(B)=0.50; t_(ret) (I)=10.8 min; FAB MS (M+H)⁺ =646.

Example 355(S)-5(S)-(6-(4-Methyl-1-piperazinyl)-3-pyridylcarbonylamino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 28, the title compound is obtained as a whitesolid, after digesting with ethyl acetate, by proceeding from 0.60 g(1.11 mmol) of 5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide fromExample 22a), 246 mg (1.12 mmol) of6-(4-methyl-1-piperazinyl)-3-pyridinecarboxylic acid (preparation, seeEP 0 385 351 A1), 0.2 ml (1.22 mmol) of diethyl cyanophosphonate and0.55 ml (3.91 mmol) of triethylamine. TLC R_(f) (B)=0.28; t_(ret)(I)=10.7 min; FAB MS (M+H)⁺ =709.

Example 365(S)-(4-(4-Morpholinylmethyl)benzoylamino-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 28, the title compound is obtained as a whitesolid, after digesting with diethyl ether, by proceeding from 1.0 g(1.84 mmol) of 5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide fromExample 22a), 523 mg (2.03 mmol) of 4-(4-morpholinylmethyl)benzoic acidhydrochloride (preparation, see Tet. Lett. 32, 7385 (1991)), 0.33 ml(2.02 mmol) of diethyl cyanophosphonate and 1.29 ml (9.22 mmol) oftriethylamine. TLC R_(f) (B)=0.60; t_(ret) (I)=11.1 min; FAB MS (M+H)⁺=709.

Example 37 5(S)-(O-4-Tetrahydropyranyl!-(L)-lactoylamino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 28, the title compound is obtained as a whitesolid, after digesting with ethyl acetate, by proceeding from 1.0 g(1.84 mmol) of 5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide fromExample 22a), 321 mg (1.88 mmol) of O- 4-tetrahydropyranyl!-(L)-lacticacid, 0.33 ml (2.02 mmol) of diethyl cyanophosphonate and 1.03 ml (7.38mmol) of triethylamine. TLC R_(f) (B)=0.72; t_(ret) (I)=14.0 min; FAB MS(M+H)⁺ =662.

The starting material is prepared in the following manner:

37a) -O- 4-Tetrahydropyranyl-(L)-lactic acid(=2(S)-(tetrahydropyran-4-yloxy)-propanoic acid)

A solution of 1.021 g (0.951 ml, d=1.074; 10 mmol) oftetrahydro-2H-pyran-4-ol (Fluka, Buchs, Switzerland) in absolute1,4-dioxane is treated, at 65° C., with 1.6 g (40 mmol) of 60% sodiumhydride in oil (Fluka, Buchs, Switzerland). The resulting, greysuspension is stirred under reflux for 2 hours and then is allowed tocool back down to 65° C., after which a solution of 1.08 g (0.863 ml, d=1.258; 10 mmol) of R(+)-2-chloropropionic acid (Fluka, Buchs,Switzerland; puriss.) in absolute 1,4-dioxane is added dropwise withinthe space of approximately 8 min. The resulting brown suspension isdiluted with dioxane so that, in the end, the reaction mixture contains55 ml of dioxane, and this mixture is then heated for 3 hours underreflux and while stirring. The mixture is subsequently stirred at roomtemperature for a further 14 hours. The brown suspension which is thusobtained is now treated dropwise with 40 ml of water within the space of2 min, and the resulting yellow solution is evaporated to dryness underHV. The residue is taken up in 200 ml of water, and the aqueous solutionis extracted once, in each case, with 250 ml and with 150 ml of ethylacetate. The organic phases are washed once with 100 ml of water. Allthe water phases are combined and then acidified (pH 1) with 4Nhydrochloric acid. The solution thus obtained is satured with sodiumchloride and extracted twice with 300 ml of ethyl acetate on eachoccasion. The organic phases are washed three times with 150 ml of asaturated solution of sodium chloride on each occasion. Subsequently,all the ethyl acetate extracts are combined, dried over magnesiumsulfate, filtered and evaporated to dryness under HV and at 30° C. Theresidue (yellow oil) is purified by kugelrohr distillation (b.p.approximately 160° C. at 0.8 mm Hg). The title compound is obtained as acolourless oil which, on standing, solidifies to give colourlesscrystals which melt between 33.7 and 67.6° C. and still contain 0.13 mol(1.30%) of water, α!_(D) ²⁰ =46.7±1.0° (c=1.035; CHCl₃).

Example 38 5(S)-(Boc-Amino)-4(S)-hydroxy6-phenyl-2(R)-(p-benzyloxyphenyl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 1, the title compound is obtained by proceedingfrom 1.29 g (1.63 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(p-benzyloxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide and1.03 g (3.26 mmol) of TBAF trihydrate. TLC R_(f) (M)=0.58; t_(ret)(I)=16.9 min.

The starting material is prepared as follows:

38a) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(p-benzyloxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 1c), the title compound is obtained as acolourless resin, after chromatographic purification on silica gel usinghexane/ethyl acetate (1:1) as eluent, by proceeding from 1.14 g (1.8mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(p-benzyloxyphenyl)methyl!hexanoic acid, 313 mg (1.8 mmol) ofH-(L)-Val-N-(2-methoxyethyl)amide (preparation, Example 1b)) and 751 mg(1.98 mmol) of HBTU in 18 ml of a 0.25 M solution of NMM inacetonitrile. TLC R_(f) (hexane/ethyl acetate (1:1))=0.19; t_(ret)(I)=23.3 min; FAB MS (M+H)⁺ =790.

38b) 5(S)- 1(S)-(Boc-Amino)-2-phenylethyl!-3(R)-(p-benzyloxyphenyl)methyl!-dihydrofuran-2-(3H)-one

In analogy with Example 1h), 1.13 g (3.70 mmol) of 5(S)-1(S)-(Boc-amino)-2-phenylethyl!dihydrofuran-2-(3H)-one Example 2b)!,dissolved in 4.8 ml of THF and 0.75 ml of1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, are deprotonated, at-75° C., with 7.25 ml of a 1M solution of lithiumbis(trimethylsilyl)amide in THF, and alkylated (15 min) with 1.2 g (3.7mmol) of p-benzyloxybenzyl iodide (Example 1d)) in 2 ml of THF. Columnchromatography (SiO₂, hexane/ethyl acetate, 2:1) affords the pure titlecompound: TLC R_(f) (D)=0.30; t_(Ret) (I)=28.2 min; FAB-MS (M+H)⁺ =502.

38c) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-benzyloxyphenyl)methyl!-hexanoic acid

In analogy with Example 1i), 1.4 g (2.79 mmol) of 5(S)-l(S)-(Boc-amino)-2-phenylethyl!-3(R)-(p-benzyloxyphenyl)methyl!dihydrofuran-2-(3H)-one in 45 ml ofdimethoxyethane and 23 ml of water are hydrolysed with 11 ml of a 1 Mlithium hydroxide solution. The reaction mixture, which has beenpartially evaporated, is poured onto a mixture of ice, 137 ml of sat.NH₄ Cl solution, 11 ml of 10% citric acid solution and 56 ml ofmethylene chloride, and methanol is added until the precipitated soliddissolves. The aqueous phase is extracted with 2 portions of methylenechloride/methanol, approximately 10:1, and the organic phases are washedwith saline, dried with Na₂ SO₄ and evaporated: t_(Ret) (I)=24.0 min;FAB-MS (M+H)⁺ =520.

38d) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(p-benzyloxyphenyl)methyl!hexanoic acid

1.4 g (2.69 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-benzyloxyphenyl)methyl!-hexanoic acid in 2.9 ml of DMF are stirred,at RT for 18 h, together with 1.87 g (12.4 mmol) oftert-butyldimethylchlorosilane and 1.5 g (22 mmol) of imidazole. Thereaction mixture is then poured onto ice water, and this mixture isextracted with 3 portions of ethyl acetate; the combined organic phasesare washed with 10% citric acid solution, water and saline, dried withsodium sulfate and evaporated. An oil is obtained. This is followed byhydrolysis of the silyl ester function of the oil, at RT, using 2.2 g ofpotassium carbonate in 63 ml of methanol/water/THF,3:1:1, and partialevaporation at RT. The aqueous residue is poured onto 10% citric acidsolution and ice, and this mixture is extracted 3 times with ethylacetate; the organic phases are washed twice with water and saline,dried with sodium sulfate and evaporated. Column chromatography (SiO₂,D) of the crude product yields the title compound: TLC R_(f) (D)=0.17;t_(Ret) (I)=33.7 min; FAB-NS (M+H)⁺ =634.

Example 395(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-hydroxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A solution of 718 mg (1.06 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-benzyloxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide fromExample 38 in 50 ml of methanol is hydrogenated, at RT for 3 h, in thepresence of 150 nag of 10% palladium on charcoal and under 1 atmhydrogen pressure. The title compound is obtained as an amorphous solidafter the catalyst has been filtered off and the filtrate has beenevaporated. TLC R_(f) (hexane/ethyl acetate (2:1))=0.29; t_(ret)(I)=12.8 min; FAB MS (M+H)⁺ =586.

Example 40 (S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-isobutoxyphenyl)-methyl!-hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A suspension consisting of 585 mg (1 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-hydroxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide fromExample 39 and 1.22 g of caesium carbonate in 50 ml of dioxane isstirred at RT for 16 h under a nitrogen atmosphere; it is then treatedwith 2.7 ml of isobutyl iodide (Fluka, Buchs, Switzerland) and heated at80° C. for 3 h until TLC monitoring can no longer detect any startingmaterials. Finally, the mixture is diluted with methylene chloride andthe precipitate is filtered off. The filtrate is evaporated and yieldsthe title compound after chromatographic purification on silica gelusing methylene chloride/methanol (95:5) as the eluent andcrystallization from ethyl acetate/hexane. TLC R_(f) (L)=0.5; t_(ret)(I)=17.1 min; FAB MS (M+H)⁺ =642.

Example 41 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-(2-pyridylmethoxy)-phenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 40, the title compound is obtained, afterchromatographic purification on silica gel using methylenechloride/methanol (97:3) as eluent and crystallization from ethylacetate, by proceeding from 65 mg of5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-hydroxyphenyl)methyl!-hexanoyl-(L)-Val-N-(2-methoxyethyl)amide fromExample 39, 137 mg of caesium carbonate and 3 ml of 2-picolyl chloride(liberated from the HCl salt (Fluka, Buchs, Switzerland) with NaHCO₃solution). TLC R_(f) (L)=0.4; t_(ret) (I)=11.7 min; FAB MS (M+H)⁺ =677.

Example 42 5(S) (Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-(3-pyridylmethoxy)-phenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A suspension consisting of 585 mg (1 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-hydroxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide fromExample 39 and 1.22 g caesium carbonate is stirred overnight, at RT andunder a nitrogen atmosphere; it is then treated with 4.0 g of 3-picolylchloride (liberated from the HCl salt (Fluka, Buchs, Switzerland) withNaHCO₃ solution) and heated at 85° C. for 6 h. After the addition of 100mg of sodium iodide and 500 mg of caesium carbonate, it is heated for afurther 18 h. For the working-up, the mixture is eluted with methylenechloride and the precipitate is filtered off. The filtrate is evaporatedand yields the title compound, as an amorphous solid, afterchromatographic purification using methylene chloride/THF (2:1) andlyophilization from dioxane. TLC R_(f) (L)=0.5; t_(ret) (I)=11.5 min;FAB MS (M+H)⁺ =677.

Example 43 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-methoxyphenyl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A solution of 90 mg (0.154 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-hydroxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide fromExample 39 in 5 ml of dioxane/DMF (1:1) is treated, at 0° C., with 100mg (0.31 mmol) of caesium carbonate and then with 0.01 ml (0.15 mmol) ofmethyl iodide. After having been stirred at RT for 14 h under a nitrogenatmosphere, the reaction mixture is poured onto ice-waters and thismixture is extracted with methylene chloride. The organic extracts arewashed with sat. sodium bicarbonate solution and saline, filteredthrough wadding and evaporated. The title compound is obtained afterchromatographic purification on silica gel using methylenechloride/methanol (19:1) and lyophilization from dioxane. TLC R_(f)(methylene chloride/methanol (19:1))=0.27; t_(ret) (I)=14.6 min; FAB MS(M+H)⁺ =600.

Example 44 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2R-(3,4-methylenedioxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A solution of 165 mg of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(3,4-methylenedioxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amidein 4.04 ml of abs. DMF is treated with 127.4 mg of TBAF, and thereaction mixture is stirred at RT for 21 h. The slightly turbid,yellowish solution is poured onto 30 ml of water, and this mixture isextracted with ethyl acetate. The organic phase is washed, so that itbecomes neutral, in succession, with sat. sodium bicarbonate solutionand saline, and dried over sodium sulfate. The title compound isdissolved in methylene chloride and precipitated with hexane. TLC R_(f)(A)=0.42; FAB-MS (M+H)⁺ =614.

The starting material is prepared as follows:

44a) 3,4-Methylenedioxybenzyl chloride

15.04 ml of thionyl chloride are added dropwise, at 0° C., over thespace of 25 min and under argon, to 10.82 g of 3,4-methylenedioxybenzylalcohol (Fluka, Buchs, Switzerland) and 48 g ofdiisopropylaminomethylpolystyrene (polyhunig base: polystyrenecrosslinked with 2% divinylbenzene, diisopropylaminomethylated; Fluka,Buchs, Switzerland) in 200 ml of abs. ether. After having been stirredat 0° C. for a further 1.5 h, the mixture is filtered with suction andthe filtrate is concentrated on a RE and then under HV. The residue ispurified by chromatography on silica gel (eluent: C), and the titlecompound thus obtained. TLC R_(f) (hexane:ethyl acetate, 4:1)=0.47; ¹H-NMR (200 MHz, CDCl₃): 6.95-6.7(m, 3H), 5.97(s, 2H), 4.53(s, 2H).

44b) 3,4-Methylenedioxybenzyl iodide

11.65 g 3,4-methylenedioxybenzyl chloride in 128 ml of abs. acetone aretreated with 49.7 g of sodium iodide, and this mixture is stirrred at RTfor 2.5 h under argon and while excluding light. The reaction mixture isdiluted with 1.5 l of ether, and this mixture is washed with 10% sodiumthiosulfate solution (600 ml) and saline. The title compound is obtainedafter drying over sodium sulfate and removing the solvent. It isrecrystallized from ether/hexane. m.p.: 51° C. TLC R_(f) (hexane:ethylacetate, 4:1)=0.43. ¹ H-NMR (360 MHz, CDCl₃): 6.93-6.77(m, 2H),6.77-6.64(m,1H), 5.95(s, 2H), 4.44 (s,2H).

44c) 5(S) 1(S)-(Boc-Amino)-2-phenylethyl!-3(R)-(3,4-methoxylenedioxyphenyl)-methyl!dihydrofuran-2-(3H)-one

Under an N₂ atmosphere, a solution of 500 mg of 5(S)-1(S)-(Boc-amino)-2-phenylethyl!-dihydrofuran-2-(3H)-one Example 2b)! in2 ml of abs. THF and 0.33 ml of1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (DMPU) is cooled downto -75° C. and treated, at an internal temperature of below -70° C.,with 3.21 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF(Aldrich, Steinheim, FRG), and this mixture is then stirred at -75° C.for 20 min. 429 mg of 3,4-methylenedioxybenzyl iodide in 1 ml of abs.ThF are added dropwise to the reaction solution within the space of 10min using a syringe, during which period the internal temperature is notallowed to exceed -70° C., and this mixture is then thoroughly stirredat -75° C. for 1 h. 0.611 ml of propionic acid are then added to theclear solution, at from -75° C. to -70° C., using a syringe, and this isfollowed by 0.611 ml of water. During this procedure, the temperaturerises to -30° C. After that the reaction mixture is diluted with 35 mlof ethyl acetate, and the whole is stirred up with 10 ml of 10% citricacid solution for 5 min in the cold (ice/water cooling). The aqueousphase is separated off and the organic phase is washed, in succession,with saline, sat. sodium bicarbonate solution, and once again withsaline. The combined aqueous phases are reextracted 2 times with ethylacetate. The combined organic phases are dried over sodium sulfate andconcentrated. The title compound is obtained as a brownish oil.Purification is effected by chromatography on silica gel (eluent D). TLCR_(f) (D)=0.38; FAB-MS (M+H)⁺ =440.

44d) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(3,4-methylenedioxyphenyl)-methyl!hexanoic acid

A solution of 278 mg of 5(S)- 1(S)-(Boc-amino)-2-phenylethyl!-3(R)-(3,4-methylenedioxyphenyl)methyl!dihydrofuran-2-(3H)-one in 10.25 ml ofethylene glycol dimethyl ether and 5.15 ml of water is treated dropwise,at RT, with 2,53 ml of a 1M lithium hydroxide solution. After that, thereaction mixture is stirred at RT for 3 h. diluted with ethyl acetateand low, and washed in a separating funnel until neutral with a mixtureconsisting of 31 ml of sat. ammonium chloride solution and 2.6 ml of 10%citric acid solution, followed by saline and water. The title compound,which is subjected to further processing without any furtherpurification, is obtained after drying over sodium sulfate and removingthe solvent. FAB-MS (M+H)⁺ =458.

44e) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(3,4-methylenedioxyphenyl)methyl!hexanoic acid

A solution of 271 mg of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(3,4-methylenedioxyphenyl)methyl!hexanoic acid in 2.13 ml of DMF istreated, while being stirred, with 338 mg of imidazole and 415 mg oftert-butyldimethylchlorosilane. After having been stirred at RT for 20h, the reaction solution is poured onto ice-water, and this mixture isextracted with ethyl acetate. The organic phase is washed with 10%citric acid solution and saline. A crude product is obtained which isdissolved in 7.13 ml of methanol and 2.75 ml of THF, with this solutionthen being treated, at RT, with a solution of 485 mg of potassiumcarbonate in 2.75 ml of water. The reaction mixture is stirred at RT for2 h, concentrated down to approximately half its volume and poured onto10% citric acid solution and ice; this mixture is then extracted withethyl acetate. The organic phase is washed with (cold) saline. Afterdrying over sodium sulfate, the solvent is evaporated and the residue ischromatographed on silica gel (eluent C), and the title compound isobtained. TLC R_(f) (C)=0.27. FAB-MS (M+H)⁺ =572.

44f) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(3,4-methylenedioxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A mixture of 120 mg of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(3,4-methylenedioxyphenyl)methyl!hexanoic acid, 87.6 mg of HBTU and 40.2mg of H-(L)-Val-N-(2-methoxyethyl)amide preparation, see Example 1b)! in1.97 ml of a 0.25 M solution of NMM in acetonitrile is stirred at RT for19 h under argon. The solution is concentrated down to half its volumeon a RE, diluted with cold ethyl acetate, and washed, in succession,with 10% citric acid, water, sat. sodium bicarbonate solution andsaline. The title compound, which is subjected to further processingwithout being purified, is obtained after drying over sodium sulfate andremoving the solvent. TLC R_(f) (D)=0.21. FAB-MS (M+H)⁺ =728.

Example 45 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(3,4-dimethoxyphenyl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 44, 136 mg of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(3,4-dimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in3.38 ml of abs. DMF are desilylated with 113.6 mg of TBAF to give thetitle compound. Purification is effected by chromatographing twice onsilica gel (eluent A, THF and methanol). The title compound isrecrystallized from methylene chloride/hexane. TLC R_(f) (A)=0.37.FAB-MS (M+H)⁺ =630.

45a) 3,4-Dimethoxybenzyl chloride

In analogy with Example 44a), the title compound is obtained from 10 gof 3,4-dimethoxybenzyl alcohol (Fluka, Buchs, Switzerland), 46.2 g ofdiisopropylaminomethylpolystyrene (polyhunig base) and 4.62 ml ofthionyl chloride in 200 ml of abs. ether. TLC R_(f) (hexane:ethylacetate 4:1)=0.31. ¹ H-NMR (200 MHz, CDCl₃): 7.0-6.87 (m, 2H); 6.82 (d,1H); 4.56 (s, 2H); 3.9 (s, 3H); 3.87 (s, 3H).

45b) 3,4-Dimethoxybenzyl iodide

In analogy with Example 44b), the title compound is obtained from 6.185g of 3,4-dimethoxybenzyl chloride and 24.19 g of sodium iodide in 62 mlof abs. acetone. TLC R_(f) (hexane:ethyl acetate 4:1)=0.40. ¹ H-NMR (200MHz, CDCl₃): 6.95 (dxd, 1H); 6.88 (d, 1H); 6.75 (d, 1H); 4.47 (s, 2H);3.87 (s, 3H); 3.86 (s, 3H).

45c) 5(S)- 1(S)-(Boc-Amino)-2-phenylethyl!-3(R)-(3,4-dimethoxyphenl)methyl!-dihydrofuran-2-(3H)-one

In analogy with Example 44c), 1 g of 5(S)-1(S)-(Boc-amino)-2-phenylethyl!dihydrofuran-2-(3H)-one Example 2b)! in 4ml of abs. THF is deprotonated (-75° C.) with 6.42 ml of a 1 M solutionof lithium bis(trimethylsilyl)amide in THF, with the addition of 0.66 mlof DMPU, and alkylated with 911 mg of 3,4-dimethoxybenzyl iodide.Chromatography on silica gel (eluents D, C and J) gives the pure titlecompound. TLC R_(f) (C)-0.42. MS M⁺ =455.

45d) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(3,4-dimethoxyphenyl)methoxy!-hexanoic acid

In analogy with Example 44d), 778 mg of 5(S)-1(S)-(Boc-amino)-2-phenylethyl!-3(R)-(3,4-dimethoxyphenyl)methyl!-dihydrofuran-2-(3H)-one in 27.67 ml ofdimethoxyethane and 13.91 ml of water are hydrolysed with 6.83 ml of 1Mlithium hydroxide solution to give the title compound, which issubjected directly to further processing. TLC R_(f) (C)=0.07.

45e) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(3,4-dimethoxyphenyl)methyl!hexanoic acid

In analogy with Example 44e), 804 mg of5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(3,4-dimethoxyphenyl)methyl!hexanoic acid in 5.94 ml of DMF aresilylated wth 1.162 g of tert-butyldimethylchlorosilane and 946.6 mg ofimidazole. The silyl ester in the crude product is cleaved at RT in 2 hin a mixture consisting of 19.61 ml of methanol, 7.56 ml of THF, 7.56 mlof water and 1.334 g of potassium carbonate. The title compound ispurified by being chromatographed twice on silica gel (eluents: D, C, Jand B). TLC R_(f) (C)=0.27. MS M⁺ =557.

45f) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(3,4-dimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 44f), 109.9 mg of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(3,4-dimethoxyphenyl)methyl!hexanoic acid, 78.1 mg of HBTU and 35.9 mgof H-(L)-Val-N-(2-methoxyethyl)amide Example 1b)! in 1.75 ml of 0.25 MNMM/CH₃ CN are reacted to yield the title compound. TLC R_(f) (A)=0.39.FAB-MS (M+H)⁺ =744.

Example 46 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(3-methoxyphenyl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 44, 300 mg of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(3-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in 6.63ml of abs. DMF are desilylated with 217.7 mg of TBAF to give the titlecompound. Purification is effected by chromatography on silica gel(eluent A and methanol), or by precipitating the substance from coldethyl acetate. TLC R_(f) (A)=0.32. FAB-MS (M+H)⁺ =600.

46a) 3-Methoxybenzyl iodide

In analogy with Example 44b), the title compound is obtained from 2 mlof 3-methoxybenzyl chloride (Fluka, Buchs, Switzerland) and 9.72 g ofsodium iodide in 23 ml of abs. acetone. TLC R_(f) (hexane/ethyl acetate,2.5:1)=0.71. ¹ H-NMR (200 MHz, CDCl₃): 7.20 (m, 1H); 7.0-6.87 (m, 2H);6.78 (dxd, 1H); 4.42 (s, 2H); 3.8 (s, 3H).

46b) 5(S)- 1(S)-(Boc-Amino)-2-phenylethyl!-3(R)-(3-methoxyphenyl)methyl!-dihydrofuran-2-(3H)-one

In analogy with Example 44c), 1.5 g of 5(S)-l(S)-(Boc-amino)-2-phenylethyl!-dihydrofuran-2-(3H)-one Example 2b)! in3 ml of abs. THF are deprotonated (-75° C.) with 9.62 ml of a 1Msolution of lithium bis(trimethylsilyl)amide in THF, and with theaddition of 0.998 ml of DMPU and alkylated with 1.22 g of3-methoxybenzyl iodide. Chromatography on silica gel (eluent E) affordsthe pure title compound. TLC R_(f) (hexane/ethyl acetate, 2.5:1)=0.32.FAB-MS (M+H)⁺ =426.

46c) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(3-methoxyphenyl)methyl!hexanoic acid

In analogy with Example 44d), 1.315 g of 5(S)-1(S)-(Boc-amino)-2-phenylethyl!-3(R)-(3-methoxyphenyl)methyl!dihydrofuran-2-(3H)-one in 49.9 ml ofdimethoxyethane and 25.16 ml of water are hydrolysed with 12.36 ml of a1M lithium hydroxide solution to give the title compound, which isdirectly subjected to further processing. TLC R_(f) (C)=0.09. FAB-MS(M+H)⁺ =444.

46d) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(3-methoxyphenyl)methyl!hexanoic acid

In analogy with Example 44e), 1.3 g of5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(3-methoxyphenyl)methyl!hexanoic acid in 13 ml of DMF are silylated with1.987 g of tert-butyldimethylchlorosilane and 1.646 g of imidazole. Thesilyl ester group in the crude product is detached at RT in 2 h in amixture consisting of 38.94 ml of methanol, 13.34 ml of THF, 13.34 ml ofwater and 2.35 g of potassium carbonate. Chromatography on silica gel(eluents: E, D and C) yields the pure title compound. TLC R_(f)(D)=0.06. FAB-MS (M+H)⁺ =558.

46e) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(3-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 44f), 200 mg of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(3-methoxyphenyl)methyl!hexanoic acid and 68.6 mg ofH-(L)-Val-N-(2-methoxyethyl)amide Example 1b)! in 3.36 ml of 0.25 MNMM/CH₃ CN are reacted with 149.4 mg of HBTU to give the title compound.TLC R_(f) (C)=0.20. FAB-MS (M+H)⁺ =714.

Example 47 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R -(2,3,4-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide##STR54##

337 mg (0.379 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amidein 7.28 ml of abs. DMF are treated with 244 mg (0.758 mmol) of TBAF, andthis mixture is stirred at RT for 20 h under argon. The reaction mixtureis diluted with approximately 50 ml of ethyl acetate, and this mixtureis washed, in succession, with water, sat. sodium bicarbonate solutionand saline. The combined aqueous phases are reextracted with ethylacetate. The combined organic phases are dried over sodium sulfate andconcentrated at approximately 30° C. The residue is dissolved in alittle ethyl acetate. Adding hexane results in the desired titlecompound being crystallized. Additional product is obtained by purifyingthe mother liquor on silica gel (eluent, ethyl acetate:methanol, 9:1).m.p.: 141-143° C. TLC R_(f) (ethyl acetate)=0.16. FAB-MS (M+H)⁺ =660.HPLC t_(Ret) =14.59 min (gradient II). IR (KBr) =inter alia, 1687, 1651,1622, 1525, 1495 and 1172 cm⁻¹. ¹ H-NMR(CD₃ OD)=inter alia, 7.30-7.10/m(5H); 6.78 and 6.63/each d (each 1H); 4.03/d (1H); 3.85, 3.81 and3.80/each s (each 3H); 1.32 and 1.26/each s (in all, 9H from Boc);0.82/pseudo t (6H).

The starting material is prepared as follows:

47a) 2,3,4-Trimethoxybenzyl chloride

5 g (24.47 mmol) of 2,3,4-trimethoxybenzyl alcohol (Aldrich, Steinheim,FRG) are dissolved, under argon, in 13.9 ml of abs. methylene chloride,and this solution is treated with 0.278 ml of pyridine . 3.05 ml ofthionyl chloride in 6.94 ml of abs. methylene chloride are addeddropwise to this solution, while cooling slightly (ice/water), withinthe period of 20 ml. During this procedure, the internal temperaturerises to approximately 18-23° C. The mixture is left to reactsubsequently for 45 min and the slightly yellow solution is then pouredonto ice/water. After the phases have been separated, the organic phaseis washed once each with 1N sulfuric acid and water. After drying overNa₂ SO₄, and removing the solvent, the oily residue is distilled underHV (b.p.: 93-95° C./0.07 Torr), and the title compound is obtained. ¹H-NMR (220 MHz, CDCl₃): 7.05 (d, 1H); 6.65 (d, 1H); 4.61 (s, 2H); 3.97(s, 3H); 3.85 (s, 3H). HPLC: t_(Ret) =8.1 min (gradient II).

47b) 2,3,4-Trimethoxybenzyl iodide

46.64 g (215.2 mmol) of 2,3,4-trimethoxybenzyl chloride in 466 ml ofabs. acetone are treated with 156.7 g (4.86 equivalents) of sodiumiodide, and this mixture is stirred at RT for 2.75 h while excludinglight. The reaction mixture is treated with approximately 3 l of (cold)ether, and the organic phase is washed once with 10% sodiumthiophosphate solution and twice with saline (both kinds of solutionsbeing cold). The combined aqueous phases are reextracted with ether. Thecombined organic phases are dried over Na₂ SO₄ and evaporated on a RE,at approximately 30° C. The residue, which is the desired titlecompound, is dried again under HV and subjected to further processing asa crude product. ¹ H-NMR (200 MHz, CDCl₃): 7.03 and 6.59 (each d; each1H); 4.47 (s, 2H); 4.05, 3.85 and 3.84 (each s, each 3H).

47c) 5(S)- 1(S)-(Boc-Amino)-2-phenylethyl!-3(R)-(2,3,4-thrimethoxyphenyl)methyl!-dihydrofuran-2-(3H)-one

A solution of 1.368 g (4.48 mmol) of 5(S)-1(S)-(Boc-amino)-2-phenylethyl!dihydrofuran-2-(3H)-one example 2b)! in 5ml of abs. THF and 0.91 ml (1.67 equivalents) of DMPU is cooled down to-75° C., under argon, and treated dropwise, at an internal temperatureof below -70° C. and over the period of approximately 20 ml, with 8.78ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF(Aldrich). After a further 15 min, a solution of 1.38 g (1 equivalent)of 2,3,4-trimethoxybenzyl iodide in 2.5 ml of abs. THF is added dropwiseto this mixture, within the period of approximately 15 min, and themixture is allowed to react at -75° C. for a further 2.25 h. For theworking-up, the reaction mixture is treated with 1.67 ml of propionicacid and 1.67 ml of water, and the temperature is allowed to rise to 0°C. The mixture is poured onto 20 ml of (cold) 10% citric acid, andapproximately 50 ml of (cold) ethyl acetate is added to this mixture.After stirring for a further 5 min, the phases are separated. Theorganic phase is washed, in succession, with saline, sat. sodiumbicarbonate solution and saline once again. The combined aqueous phasesare reextracted twice with ethyl acetate. The combined organic phasesare dried over Na₂ SO₄ and concentrated. The residue which remains afterremoving the solvent is chromatographed on silica gel (hexane:ethylacetate, 3:1), and the title compound thereby obtained. HPLC t_(Ret)=16.49 min (gradient II). FAB-MS (M+H)⁺ =486 and M⁺ =485. IR(KBr)=interalia, 3312, 1759, 1686, 1603, 1537, 1165 and 1104 cm⁻¹. ¹ H-NMR(CD₃OD)=inter alia, 7.30-7.10 (m, 5H); 6.84 and 6.66 (each d, each 1H);3.85, 3.82 and 3.87 (each s, each 3H); 1.30 (s, 9H).

47d) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)-methyl!hexanoic acid

A solution of 1.354 g (2.685 mmol) of 5(S)-1(S)-(Boc-amino)-2-phenylethyl!-3(R)-(2,3,4-trimethoxyphenyl)methyl!dihydrofuran-2-(3H)-one in 43.36 ml ofdimethoxyethane and 21.86 ml of water is treated, at RT, with 10.74 mlof a 1M solution of lithium hydroxide in water, and this reactionmixture is stirred for 2 h. It is then transferred to a separatingfunnel, diluted with 132 ml of sat. ammonium chloride solution and 11 mlof a 10% citric acid solution (both cold), and this mixture is thenextracted with ethyl acetate and a little THF. The title compound, whichis dried under HV and subjected to further processing without beingpurified, is obtained after washing the organic phase with (cold) salineand drying it over sodium sulfate. TLC R_(f) (C)=0.03. MS (M-H₂ O)⁺=485.

47e) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoic acid

A solution of 1.308 g (2.597 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoic acid, 1.443 g (20.776 mmol) ofimidazole and 1.816 g (11.686 mmol) of tert-butyldimethylchlorosilane in13 ml of abs. DMF is stirred at RT for 17 h under argon. After that, thereaction mixture is poured onto ice-water and this mixture is extractedwith ethyl acetate. The organic phase is washed with cold 10% citricacid solution and saline. The combined aqueous phases are reextractedwith ethyl acetate. The combined organic phases are dried over sodiumsulfate and evaporated on a RE at approximately 30° C. The resultingproduct is dissolved in 34.51 ml of methanol and 11.82 ml of THF, andthis solution is treated, at RT, with 2.08 g of potassium carbonate in11.82 ml of water. After it has been stirred for 2.5 h, the reactionmixture is concentrated down, at approximately 30° C., to half itsvolume and treated with ethyl acetate and 10% citric acid solution(cold), and the phases are separated. The organic phase is washed afurther two times with (cold) saline. The combined aqueous phases arereextracted with ethyl acetate. The combined organic phases are driedover Na₂ SO₄ and concentrated. The residue is purified by chromatographyon silica gel (hexane:ethyl acetate, 1:1 and then 1:1.5), and the titlecompound is obtained. TLC R_(f) (J)=0.02. FAB-MS (M+H)⁺ =618 IR(KBr)inter alia: 1712, 1495, 1366, 1101 and 836 cm⁻¹. ¹ H-NMR(CD₃ OD) interalia: 7.30-7.10 (m, 5H); 6.84 and 6.67 (each d, each 1H); 6.23 and 5.55(each d, in all 1H from NH); 3.86, 3.81 and 3.80 (each s, each 3H); 1.31and 1.20 (each s, in all 9H from Boc); 0.93 (s, 9H); 0.14 and 0.11 (eachs, each 3H).

47f) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,3,4-trimethoxy-phenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A mixture of 250 mg (0.405 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoic acid, 168.8 mg (0.445 mmol) ofHBTU and 77.55 mg (0.445 mmol) of H-(L)-Val-N-(2-methoxyethyl)amideExample 1b)! in 3.8 ml of a 0.25 M solution of NMM in acetonitrile (2.35equivalents) is stirred for 21 h under argon and at RT. After that, thereaction mixture is concentrated on a RE at approximately 30° C., andthe residue is taken up in ethyl acetate; this solution is washed, insuccession, with 10% citric acid solution, water, sat. sodiumbicarbonate solution and saline (all being cold). The combined aqueousphases are reextracted with ethyl acetate. The combined organic phasesare dried over Na₂ SO₄ and concentrated. The crude product (titlecompound) is subjected to further processing without purification. TLCR_(f) (A)=0.57. FAB-MS (M+H)⁺ =774. HPLC t_(Ret) =21.68 min (gradientII). IR(KBr)=inter alia 1711, 1653, 1495, 1468, 1100 and 836 cm⁻¹. ¹-NMR(CD₃ OD)=inter alia, 7.3-7.1 (m, 5H); 6.79 and 6.65 (each d, each1H); 5.93 and 5.57 (each d, in all 1H from NH); 3.87, 3.83 and 3.80(each s, each 3H); 3.35 (s, 2H); 1.30 and 1.20 (each s, in all 9H fromBoc); 0.96 (s, 9H); 0.90 and 0.87 (each 3H); 0.18 and 0.16 (each s, each3H).

Alternatively, the compound described in Example 47 can also be readilyobtained in the following manner see, in this context, J. Med. Chem. 37,2991 (1994)!:

47g) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

1 g (2.06 mmol) of 5(S)- 1(S)-(Boc-amino)-2-phenylethyl!-3(R)-(2,3,4-trimethoxyphenyl)methyl!dihydrofuran-2-(3H)-one prepared inaccordance with Example 47c)! and 2.51 g (7 equivalents) ofH-(L)-Val-N-(2-methoxyethyl)amide prepared in accordance with Example1b)! are reacted, at 70° C. for 18 h, with 0.354 ml (3 equivalents) ofacetic acid in a bomb tube. The mixture is allowed to cool down and theresidue is taken up in ethyl acetate, and the organic phase is washed,in succession, with 1N hydrochloric acid, water and saline. After dryingover sodium sulfate and removal of the solvent, the residue isrecrystallized from ethanol/water. The resulting compound is identicalto the title compound described in Example 47.

Another alternative method for preparing the title compound from Example47:

47h) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

500 mg (1.03 mmol) of 5(S)- 1(S)-(Boc-amino)-2-phenylethyl!-3(R)-(2,3,4-trimethoxy phenyl)methyl!dihydrofuran-2-(3H)-one prepared inaccordance with Example 47c)! and 538.5 mg (3 equivalents) ofH-(L)-Val-N-(2-methoxyethyl)amide prepared in accordance with Example1b)! are reacted, at 90° C. for 40 h, with 101 mg (1 equivalent) of2-hydroxypyridine in a bomb tube. The residue is taken up in 4 ml ofethanol and poured onto 50 ml of water, and this mixture is stirred for2 h. The crystalline precipitate is filtered off with suction, washedwith water and dried. The resulting compound is identical to the titlecompound described in Example 47.

Alternatively, and in a manner analogous to that indicated in Example47c), the title compound described in that example can also be preparedusing 2,3,4-trimethoxybenzyl bromide (instead of 2,3,4-trimethoxybenzyliodide). The 2,3,4-trimethoxybenzyl bromide is prepared in the followingmanner:

47i) 2,3,4-Trimethoxybenzyl bromide

2.04 g (10 mmol) of 2,3,4-trimethoxybenzyl alcohol in 30 ml of abs.toluene are treated with 0.258 ml (0.32 equivalents) of pyridine, andthe solution is cooled down to approximately 4° C. using ice-water.0.951 ml of phosphorus tribromide in 5 ml of abs. toluene is addeddropwise, at this temperature and over the period of 30 min, to thissolution, which is left to stir at this temperature for a further 45 ml.The reaction mixture is diluted with ether and the whole is poured ontoice-water, with this mixture then being stirred for 5 min. After thephases have been separated, the organic phase is washed, in succession,with water, saline, sat. sodium bicarbonate solution and once again withsaline (all being cold). After the organic phase has been dried oversodium sulfate, it is concentrated, and residual solvents are removedfrom the residue under high vacuum for 1 h. The resulting title compoundis subjected, without purification, to further processing. ¹ H-NMR (200MHz; CDCl₃) =7.05/d (1H); 6.65/d (1H); 4.55/s (2H); 4.07, 3.88 and3.85/each s (each 3H).

Example 48 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 44, 191 mg of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(3,4,5-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amidein 4.6 ml of abs. DMF are desilylated with 159 mg of TBAF to give thetitle compound. The crude product is purified by chromatography onsilica gel (eluent A), dissolved in dioxane and lyophilized. TLC R_(f)(A)=0.26. FAB-MS (M+H)⁺ =660.

The starting material is prepared as follows:

48a) 3,4,5-Trimethoxybenzyl iodide

In analogy with Example 44b), the title compound is obtained from 5 g of3,4,5-trimethoxybenzyl chloride (Fluka, Buchs, Switzerland) and 16.89 gof sodium iodide in 40 ml of abs. acetone. TLC R_(f) (hexane:ethylacetate, 4:1)=0.27. ¹ -NMR (360 MHz, CDCl₃): 6.60 (s, 2H); 4.44 (s, 2H);3.86 (s, 6H); 3.83 (s, 3H).

48b) 5(S)- 1(S)-(Boc-Amino)-2-phenylethyl-3(R)-(3,4,5-trimethoxyphenyl)methyl!-dihydrofuran-2-(3H)-one

In analogy with Example 44c), 1 g of 5(S)1(S)-(Boc-amino)-2-phenylethyl!-dihydrofuran-2-(3H)-one Example 2b)! in4 ml of abs. THF is deprotonated (-75° C.) with 6.42 ml of a 1 Msolution of lithium bis(trimethylsilyl)amide in THF, and with theaddition of 0.66 ml of DMPU and alkylated with 1.008 g3,4,5-trimethoxybenzyl iodide. Chromatography on silica gel (eluent,hexane/acetone 3:1) affords the title compound. TLC R_(f)(hexane/acetone, 3:1)=0.22. FAB-MS M⁺ =485.

48c) 5(S)-(Boc-Amino)-4(S)hydroxy-6-phenyl-2(R)-(3,4,5-trimethoxyphenyl)-methyl!hexanoic acid

In analogy with Example 44d), 1.097 g of 5(S)-1(S)-(Boc-amino)-2-phenylethyl!-3(R)-(3,4,5-trimethoxyphenyl)methyl!dihydrofuran-2-(3H)-one in 36.48 ml ofdimethoxyethane and 18.39 ml of water are hydrolysed with 9.03 ml of 1Mlithium hydroxide solution to give the title compound, which issubjected, without purification, to further processing.

48d) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-3,4,5-trimethyloxyphenyl)-methyl!hexanoic acid

In analogy with Example 44e), 1.526 g of5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(3,4,5-trimethoxyphenyl)methyl!hexanoic acid in 15.16 ml of DMF aresilylated with 2.11 g of tert-butyldimethylchlorosilane and 1.683 g ofimidazole. The silyl ester group in the crude product is detached, at RTin 2.5 h, in a mixture consisting of 40.3 ml of methanol, 13.8 ml ofTHF, 13.8 ml of water and 2.42 g of potassium carbonate. The titlecompound is purified by being chromatographed twice on silica gel(solvents: hexane, C and J). TLC R_(f) (A)=0.39. FAB-MS (M+H)⁺ =618.

48e) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(3,4,5-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 44f), 202 mg of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(3,4,5-trimethoxyphenyl)methyl!hexanoic acid and 62.6 mg ofH-(L)-Val-N-(2-methoxyethyl)amide prepared in accordance with Example1b)! in 3.07 ml of 0.25 M NMM/CH₃ CN are reacted with 136.4 mg of HBTU,and with a further 24.8 mg of HBTU, to form the title compound, which issubjected, without purification, to further processing, after a reactiontime of 20 h. TLC R_(f) (A)=0.32. FAB-MS (M+H)⁺ =774.

Example 49 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,4-dimethoxyphenyl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

599 mg (0.805 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,4-dimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in15.5 ml of abs. DMF are treated with 508 mg (1.61 mmol) of TBAF and thereaction mixture is stirred at RT for 20 h under argon. It is thendiluted with approximately 80 ml of ethyl acetate, and the whole iswashed, in succession, with water, sat. sodium bicarbonate solution andsaline. The combined aqueous phases are reextracted with ethyl acetate.The combined organic phases are dried over Na₂ SO₄ and concentrated downto approximately 30 ml on a RE. During this procedure, the titlecompound precipitates in pure form. The latter is filtered off withsuction, washed with hexane and dried to constant weight. TLC R_(f)(A)=0.28.-FAB-MS (M+H)⁺ =630.-HPLC t_(Ret) =14.79 min (gradientII).-IR(KBr)=inter alia 3463, 3340, 3305, 1685, 1648, 1620 und 1524cm⁻¹.-¹ H-NMR(CD₃ OD)=inter alia 7.29-7.09/m (5H); 6.90/d (1H); 6.46/d(1H); 6.35/dxd (1H); 4.01/d (1H); 3.80 and 3.75/each s (each 3H); 3.30/s(3H); 1.35/s (9H); 0.83/pseudo t (6H).

The starting material is prepared as follows:

49a) 2,4-Dimethoxybenzyl bromide

2 g (11.77 mmol) of 2,4-dimethoxybenzyl alcohol (Aldrich, Steinheim,FRG) are dissolved in 30 ml of abs. toluene, and this solution istreated with 0.3 ml of pyridine. The clear solution is cooled down toapproximately 4° C. and 1.12 ml (0.992 equivalents) of PBr3 in 6 ml ofabs. toluene are added dropwise to it over the space of 30 min. After afurther 45 min, the reaction solution is poured onto ice-water and thewhole is extracted with ether. The organic phase is washed, insuccession, with water, sat. sodium bicarbonate solution and saline (allbeing cold). The combined aqueous phases are reextracted with ether. Thecombined organic phases are dried over Na₂ SO₄ and the ether is removedon a RE at about 30° C. The toluene solution which remains, and whichcontains the title compound, is immediately subjected to further use.TLC (hexane:ethyl acetate, 1:1): decomposition.

49b) 5(S)- 1(S)-(Boc-Amino)-2-phenylethyl!-3(R)-(2,4-dimethoxyphenyl)methyl!-dihydrofuran-2-(3H)-one

A solution of 3.57 g (11.7 mmol) of 5(S)-1(S)-(Boc-amino)-2-phenylethyl!dihydrofuran-2-(3H)-one Example 2b)! in12 ml of abs. THF and 2.35 ml of DMPU (1.65 equivalents) is cooled downto -75° C., under argon, and is treated dropwise, at an internaltemperature of less than -70° C. and over a period of 30 min, with 22.9ml (1.96 equivalents) of a 1 M solution of lithiumbis(trimetlhylsilyl)amide in THF (Aldrich, Steinheim, FRG). After afurther 15 min, 25 ml of a toluene solution containing approximately 1equivalent of 2,4-dimethoxybenzyl bromide is added dropwise to thismixture, over the space of 20 min, and this mixture is allowed to reactat -70° C. for 2 h. 4.36 ml of propionic acid and 4.36 ml of water arethen added to this solution and the temperature is allowed to rise to 0°C. The reaction mixture is diluted with 200 ml of (cold) ethyl acetateand stirred up for 5 min with 60 ml of (cold) 10% citric acid. Afterthat, the phases are separated. The organic phase is washed, insuccession, with saline, sat. sodium bicarbonate solution and withsaline once again, dried over Na₂ SO₄ and concentrated. The titlecompound is isolated by flash chromatography on silica gel (E). TLCR_(f) (E)=0.24.-FAB-MS (M+H)⁺ =455.-HPLC t_(Ret) =16.85 min (gradientII). IR(CH₂ Cl₂)=inter alia 3429, 1769, 1712, 1613 and 1506 cm⁻¹.-¹H-NMR(CDCl₃)=inter alia 7.34-7.10/m (5H); 6.98/d (1H); 6.45-6.29/m (2H);4.31/txd (1H); 3.78 and 3.71/each s (each 3H); 3.08 and 2.66/each dxd(each 1H); 1.35/s (9H).

49c) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,4-dimethoxyphenyl)methyl!-hexanoic acid

A solution of 1.58 g (3.47 mmol) of 5(S)-1(S)-(Boc-amino)-2-phenylethyl!-3(R)-(2,4-dimethoxyphenyl)methyl!dihydrofuran-2-(3H)-one in 56 ml of ethyleneglycol dimethyl ether and 28.2 ml of water is treated, at RT, with 13.87ml of a 1M solution of LiOH in water, and this mixture is stirred for1.75 h. After that, the reaction mixture is diluted with ethyl acetateand a little THF and the whole is washed firstly with a mixtureconsisting of 170.6 ml of sat. ammonium chloride solution and 14.25 mlof 10% citric acid solution (both being cold) and then with saline. Thecombined aqueous phases are reextracted with ethyl acetate. The combinedorganic phases are dried over Na₂ SO₄ and evaporated on a RE at about30° C. The residue, which is the title compound, is triturated withhexane and filtered off with suction. M.p.: 144-145 C.-TLC R_(f) (D)=atthe start.-FAB-MS (M+H)⁺ =474.-HPLC t_(Ret) =14.34 min (gradientII).-IR(KBr) =u.a. 3420, 3350, 2818, 1686, 1518 and 1508 cm⁻¹.-¹H-NMR(CD₃ OD)=inter alia 7.30-7.09/m (5H); 6.94/d (1H); 6.47/d (1H);6.37/dxd (1H); 3,78 and 3.75/each s (each 3H); 1.33/s (9H).

49d) 5(S)-(Boc-Amino)-4S-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,4-dimethoxyphenyl)methyl!hexanoic acid

A solution of 1.5 g (3.17 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,4-dimethoxyphenyl)methyl!hexanoic acid, 1.76 g (25.36 mmol) ofimidazole and 2.22 g (14.26 mmol) of tert-butyldimethylchlorosilane in16 ml of abs. DMF is stirred at RT for 20 h under argon. After that, thereaction mixture is poured onto ice-water and the whole is extractedwith ethyl acetate. The organic phase is washed with cold 10% citricacid solution and saline. The combined aqueous phases are reextractedwith ethyl acetate. The combined organic phases are dried over Na₂ SO₄,and the solvent is removed on a RE at about 30° C. An oil is obtainedwhich is dissolved in 42.1 ml of methanol and 14.4 ml of THF, and thissolution is then treated, at RT, with 2.5 g of potassium carbonate in14.4 ml of water. After it has been stirred at RT for 2 h, the reactionmixture is concentrated down to half its volume at approximately 30° C.and the residue is diluted with ethyl acetate; the whole is then washedwith 10% citric acid solution and with saline (both being cold). Thecombined aqueous phases are reextracted with ethyl acetate. The combinedorganic phases are dried over Na₂ SO₄ and evaporated. Chromatography onsilica gel (D) affords the pure title compound. TLC R_(f)(C)=0.34.-FAB-MS (M+H)⁺ =588.-HPLC t_(Ret) =20.24 min (gradientII).-IR(KBr)=inter alia 1712, 1654, 1614, 1588 und 1507 cm⁻¹.-¹H-NMR(CD₃ OD)=inter alia 7.30-7.10/m (5H); 6.98/d (1H); 6.50/d (1H);6.40/dxd (1H); 3.80 and 3.76/each s (each 3H); 1.31/s (9H); 0.93/s (9H);0.14 and 0.11/each s (each 3H).

49e) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,4-dimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A mixture of 497 mg (0.845 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,4-dimethoxyphenyl)methyl!hexanoic acid, 352 mg (0.929 mmol) of HBTUand 162 mg (0.929 mmol) of H-(L)-Val-N-(2-methoxyethyl)amide Example1b)! in 7.94 ml of a 0.25 M solution of NMM in acetonitrile (2.35equivalents) is stirred at RT for 20 h under argon. After that, thereaction mixture is concentrated on a RE at about 30° C. and the residueis taken up in ethyl acetate, with this solution being washed with sat.sodium bicarbonate solution and saline. The combined aqueous phases arereextracted with ethyl acetate. The combined organic phases are driedover Na₂ SO₄, and the solvent is removed on a RE. The residue consistsof the title compound in virtually pure form. TLC R_(f) (J)=0.25.-FAB-MS(M+H)⁺ =744.-HPLC t_(Ret) =21.55 min (gradient II).-IR(CH₂ Cl₂)=interalia 3434, 1703, 1667, 1506 and 838 cm⁻¹.-¹ H-NMR(CD₃ OD)=inter alia7.31-7.11/m (5H); 6.91/d (1H); 6.50/d (1H); 6.37/dxd (1H); 3.84 and3.76/each s (each 3H); 3.31/s (3H); 1.30/s (9H); 0.94/s (9H); 0.85 and0.83/each d (each 3H); 0.16 and 0.15/each s (each 3H).

Example 50 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(2-methoxyphenyl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

311 mg (0.436 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in 8.4ml of abs. DMF are treated with 275 mg (0.871 mmol) of TBAF, and thisreaction mixture is stirred at RT for 21 h under argon. It is thendiluted with approximately 60 ml of ethyl acetate, and the whole iswashed, in succession, with water, sat. sodium bicarbonate solution andsaline. The combined aqueous phases are reextracted with ethyl acetate.The combined organic phases are dried over Na₂ SO₄ and concentrated downto 10 ml on a RE at approximately 30° C. During this procedure, thetitle compound is precipitated in pure form. It is filtered off withsuction, washed with hexane and dried overnight under HV. TLC R_(f)(ethyl acetate)=0.38.-FAB-MS (M+H)⁺ =600.-HPLC t_(Ret) =14.78 min(gradient II).-IR(KBr)=inter alia 3335, 1685, 1653, 1619, and 1526cm⁻¹.-¹ H-NMR(CD₃ OD)=inter alia 7.28-7.06/m (6H); 7.00/d (1H); 6.88/d(1H); 6.76/t (1H); 3.81/s (3H); 3.48/s (3H); 1.33/s (9H); 0.81/pseudo t(6H).

The starting material is prepared as follows:

50a) 2-Methoxybenzyl chloride

16.8 ml of thionyl chloride are added dropwise, over the space ofapproximately 30 min, to 10 ml of 2-methoxybenzyl alcohol (Fluka, Buchs,Switzerland) and 53.76 g of diisopropylaminomethylpolystyrene (polyhunigbase, see Ex. 44a)) in 200 ml of abs. ether. After the mixture has beenstirred at 0° C. for a further 1.5 h, it is filtered with suction andthe filtrate is concentrated on a RE and under HV. The residue ispurified by chromatography on silica gel (eluent: hexane/ethyl acetate,6:1). TLC R_(f) (hexane:ethyl acetate=4:1)=0.5. ¹ H-NMR (200 MHz,CDCl₃): 7.42-7.24 (m, 2H); 7.0-6.84 (m, 2H); 4.68 (s, 2H); 3.9 (s, 3H).

50b) 2-Methoxybenzyl iodide

2 g of 2-methoxybenzyl chloride in 22 ml of abs. acetone are treatedwith 9.3 g of sodium iodide and the reaction mixture is stirred at RTovernight. It is then diluted with 250 ml of ether and the whole iswashed with 10% sodium thiosulfate solution and saline. After dryingover sodium sulfate, and removing the solvent, the title compound, whichis subjected, without purification, to further processing, is obtained.TLC R_(f) (hexane:ethyl acetate=4:1)=0.46. ¹ H-NMR (200 MHz, CDCl₃):7.36-7.2 (m, 2H); 6.92-6.8 (m, 2H); 4.48 (s, 2H); 3.91 (s, 3H).

50c) 5(S)- 1(S)-(Boc-Amino)-2-phenylethyl!-3(R)-(2-methoxyphenyl)methyl!-dihydrofuran-2-(3H)-one

A solution of 1 g (3.275 mmol) of 5(S)-1(S)-(Boc-amino)-2-phenylethyl!dihydrofuran-2-(3H)-one Example 2b)! in 4ml of abs. THF and 0.66 ml of DMPU (1.67 equivalents) is cooled down to-75° C., under argon, and treated dropwise, at an internal temperatureof below -70° C. and over the space of 30 min, with 6.42 ml (1.96equivalents) of a 1M solution of lithium bis(trimethylsilyl)amide in THF(Aldrich, Steinheim, FRG). After a further 15 min, 812 mg (3.275 mmol)of 2-methoxybenzyl iodide, dissolved in 2 ml of THF, are added dropwiseto this mixture within the space of 10 min, and the whole is allowed toreact at -70° C. for 2 h. 1.22 ml of propionic acid and 1.22 ml of waterare subsequently added to this solution, and the temperature is allowedto rise to 0° C. The reaction mixture is diluted with 50 ml of (cold)ethyl acetate and stirred, for 5 min, with 20 ml of (cold) 10% citricacid, and, after that, the phases are separated. The organic phase iswashed, in succession, with saline, sat. sodium bicarbonate solution andonce again with saline, dried over Na₂ SO₄ and concentrated. The titlecompound is isolated by means of flash chromatography on silica gel(hexane:ethyl acetate=3:1). TLC R_(f) (hexane:ethylacetate=3:1)=0.54.-MS M⁺ =455.-HPLC t_(Ret) =17.09 min (gradientII).-IR(CH₂ Cl₂)=inter alia 3429, 1769, 1712, and 1495 cm⁻¹.-¹H-NMR(CDCl₃)=inter alia 7.38-7.13/m (5H); 7.20/d (1H); 7.08/d (1H);6.87/t (1H); 6.81/d (1H); 3.74/s (3H); 1.34/s (9H).

50d) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(2-methoxyphenyl)methyl!-hexanoic acid

A solution of 474 mg of 5(S)- 1(S)-(Boc-amino)-2-phenylethyl!-3 (R)-(2-methoxyphenyl)methyl!dihydrofuran-2-(3H)-one in 18 ml ofdimethoxyethane and 9.07 ml of water is treated dropwise, at RT, with4.45 ml of a 1M lithium hydroxide solution. After that, the reactionmixture is stirred at RT for 3 h and diluted with ethyl acetate and THF,and the whole is washed in a separating funnel until neutral with amixture consisting of 54.78 ml of sat. ammonium chloride solution and4.58 ml of 10% citric acid solution, followed by saline and water. Thetitle compound, which is subjected to further processing without anyfurther purification, is obtained after drying over sodium sulfate andremoving the solvent. TLC R_(f) (hexane/ethyl acetate 2.5:1)=0.15.

50e) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2-methoxyphenyl)methyl!hexanoic acid

A solution of 500 mg of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(2-methoxyphenyl)methyl!hexanoic acid in 5 ml of DMF is treated, whilebeing stirred, with 614 mg of imidazole and 796 mg oftert-butyldimethylchlorosilane. After it has been stirred at RT for 20h, the reaction solution is poured onto ice-water and the whole isextracted with ethyl acetate. The organic phase is washed with 10%citric acid solution and saline. The silyl ester group in the crudeproduct is detached, at RT in 2 h, in a mixture consisting of 13.29 mlof methanol, 5.13 ml of THF, 5.13 ml of water and 904 mg of potassiumcarbonate. The mixture is concentrated down to half its volume on a REat approximately 30° C., and the residue is diluted with ethyl acetate,and the organic phase is washed with 10% citric acid and saline (allbeing cold). The combined aqueous phases are reextracted with ethylacetate. The combined organic phases are dried over sodium sulfate andthe residue is chromatographed on silica gel (eluent, hexane:ethylacetate, 3:1 and 1:1), and the title compound is obtained. TLC R_(f)(hexane/ethyl acetate 2.5:1)=0.12. FAB-MS (M+H)⁺ =558.

50f) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A mixture of 250 mg (0.448 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2-methoxyphenyl)methyl!hexanoic acid, 187 mg (0.493 mmol) of HBTU and86 mg (0.493 mmol) of H-(L)-Val-N-(2-methoxyethyl)amide Example 1b)! in4.2 ml of a 0.25 M solution of NMM in acetonitrile (2.35 equivalents) isstirred at RT for 20 h under argon. After that, the reaction mixture isconcentrated on a RE at approximately 30° C. and residue is taken up inethyl acetate, and the whole is washed, in succession, with 10% citricacid solution, sat. sodium bicarbonate solution and saline (all beingcold). The combined aqueous phases are reextracted with ethyl acetate.The combined organic phases are dried over Na₂ SO₄ and the solvent isremoved on a RE. The residue consists of the title compound in virtuallypure form. TLC R_(f) (hexane:ethyl acetate 1:2)=0.29.-FAB-MS (M+H)⁺=714.-HPLC t_(Ret) =21.66 min (gradient II).-IR(CH₂ Cl₂)=inter alia3435, 1704, 1667, 1495 and 836 cm⁻¹.-¹ H-NMR(CD₃ OD)=inter alia7.29-7.10/m (6H); 7.02/d (1H); 6.91/d (1H); 6.80/t (1H); 3.86/s (3H);3.30/s (3H); 1.31/s (9H); 0.93/s (9H); 0.85/d (6H); 0.16 and 0.15/each s(each 3H).

Example 51 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3-dimethyl-4-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

323.5 mg (0.436 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,3-dimethyl-4-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)-amidein 8.4 ml of abs. DMF are treated with 280.7 mg (0.872 mmol) of TBAF,and this reaction mixture is stirred at RT for 20 h under argon. It isthen diluted with approximately 80 ml of ethyl acetate and the whole iswashed, in succession, with water, sat. sodium carbonate solution andsaline. The combined aqueous phases are reextracted with ethyl acetate.The combined organic phases are dried over sodium sulfate andconcentrated. The resulting gel-like product is chromatographed onsilica gel (hexane:ethyl acetate, 1:2). The product-containing fractionsare pooled and concentrated. The residue is dissolved in dioxane andlyophilized, with the title compound being obtained. TLC R_(f)(hexane:ethyl acetate 1:2)=0.18. FAB-MS (M+H)⁺ =628. HPLC t_(Ret) =15.52min (gradient II). IR(KBr)=inter alia 1688, 1650, 1619, 1519 and 1261cm⁻¹. ¹ H-NMR(CD₃ OD)=inter alia 7.31-7.10 (m, 5H); 6.87 and 6.63 (eachd, each 1H); 4.03 (d, 1H); 3.75, 2.20 and 2.11 (each s, each 3H); 1.35(s, 3H); 0.83 (pseudo t, 6H).

The starting material is prepared as follows:

51a) 2,3-Dimethyl-4-methoxybenzyl chloride

1 g (6.016 mmol) of 2,3-dimethyl-4-methoxybenzyl alcohol (Aldrich,Steinheim, FRG) and 4.8 g of diisopropylaminomethylpolystyrene(polyhunig base, see Ex. 44a) in 21 ml of abs. ether are treateddropwise, at from 0° C. to 5° C. and over the space of approximately 25min, with 0.482 ml of thionyl chloride. After the reaction has ended,the mixture is filtered with suction and the solvent and the excessreagent are removed. The residue, which is the desired title compound,is subjected, without purification, to further processing. TLC R_(f)(hexane:ethyl acetate 4:1)=0.59. IR(CH₂ Cl₂) inter alia: 1599, 1485,1466 und 1107 cm⁻¹. ¹ H-NMR (200 MHz, CDCl₃): 7.14 (d, 1H); 6.69 (d,1H); 4.64 (s, 2H); 3.82, 2.34 and 2.18 (each s, each 3H).

51 b) 2,3-Dimethyl-4-methoxybenzyl iodide

838.6 mg (4.54 mmol) of 2,3-dimethyl-4-methoxybenzyl chloride in 8.5 mlabs. acetone are treated with 3.328 g (22.1 mmol) of sodium iodide, andthis mixture is stirred at RT for 15 h while excluding light. Adark-brown suspension is obtained which is taken up, for working-up, in100 ml of diethyl ether with this solution then being washed with 10%sodium thiosulfate solution. After drying with sodium sulfate andremoving the solvent, the desired title compound is obtained as ayellowish solid which is subjected, without purification, to furtherprocessing. TLC R_(f) (hexane:ethyl acetate 4:1)=0.63. IR (CH₂ Cl₂)inter alia: 1610, 1495, 1120 and 820 cm⁻¹. ¹ H-NMR (200 MHz, CDCl₃):7.17 and 6.65 (each d, each 1H); 4.52 (s, 2H); 3.82, 2.23 and 2.18 (eachs, each 3H).

51c) 5(S)- 1(S)-(Boc-Amino)-2-phenylethyl!-3(R)-(2,3-dimethyl-4-methoxyphenyl)-methyl!dihydrofuran-2(3H)-one

A solution of 1.248 g (4.087 mmol) of 5(S)-1(S)-(Boc-amino)-2-phenylethyl!dihydrofuran-2-(3H)-one (Example 2b)) in5 ml of abs. THF and 0.823 ml (6.825 mmol) of DMPU is cooled down to-75° C., under argon, and treated dropwise, at an internal temperatureof below -70° C. and over the space of approximately 17 min, with 8 mlof a 1M solution of lithium bis(trimethylsilyl)amide in THF (Aldrich).After a further 15 min, a solution of 1.128 g (4.087 mmol) of2,3-dimethyl-4-methoxybenzyl iodide in 3 ml of abs. THF is addeddropwise to this mixture within the space of 10 min, and the whole isallowed to react at -75° C. for a further 2 h. For the working-up, thereaction mixture is treated with 1.5 ml of propionic acid and 1.5 ml ofwater and the temperature is allowed to rise to 0° C. The mixture ispoured onto 35 ml of (cold) 10% citric acid solution, and approximately70 ml of (cold) ethyl acetate is added to this mixture. After stirringfor a further 5 min, the phases are separated. The organic phase iswashed, in succession, with saline, sat. sodium bicarbonate solution andwith saline once again, dried over Na₂ SO₄ and concentrated. The residuewhich remains after removing the solvent is chromatographed on silicagel (hexane:ethyl acetate, 2:1). The title compound is obtained as acolourless foam. TLC R_(f) (hexane:ethyl acetate 2:1)=0.37. HPLC t_(Ret)=17.83 min (gradient II). FAB-MS (M+H)⁺ =453. IR(CH₂ Cl₂)=inter alia3428, 1769, 1712 and 1495 cm⁻¹. ¹ H-NMR(CDCl₃)=inter alia 7.38-7,08 (m,5H); 6.86 and 6.62 (each d, each 1H); 3.78 (3H); 3.21 and 2.16 (eachdxd, each 1H); 2.19 and 2.13 (each s, each 3H); and 1.35 (s, 9H).

51d) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3-dimethyl-4-methoxyphenyl)-methyl!hexanoic acid

A solution of 1.001 g (2.2 mmol) of 5(S)-1(S)-(Boc-amino)-2-phenylethyl!-3(R)-(2,3-dimethyl-4-methoxyphenyl)methyl!dihydrofuran-2-(3H)-one in 35.8 mlof dimethoxyethane and 18 ml of water is treated, at RT, with 8.8 ml ofa 1M solution of lithium hydroxide in water, and this reaction mixtureis stirred for 2.5 h. It is then transferred to a separating funnel anddiluted with 108.5 ml of sat. ammonium chloride solution and 9 ml of a10% citric acid solution (both being cold); the whole is then extractedwith ethyl acetate and a little THF. The title compound, which issubjected to further processing without being purified, is obtainedafter washing the organic phase with (cold) saline and drying it oversodium sulfate. TLC R_(f) (hexane:ethyl acetate 1:1)=at the start.FAB-MS (M+H)⁺ =472; IR(KBr) inter alia: 1724, 1666, 1527 and 1169 cm⁻¹.¹ H-NMR(CD₃ OD) inter alia: 7.31-7.11 (m, 5H); 6.93 and 6.68 (each d,each 1H); 3.76 (s, 3H); 3.23 and 2.59 (each dxd, each 1H); 2.21 and 2.12(each s, each 3H); 1.27 (s, 9H).

51e) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,3-dimethyl-4-methoxyphenyl)methyl!hexanoic acid

A solution of 1.153 g (2.445 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3-dimethyl-4-methoxyphenyl)methyl!hexanoic acid, 1.372 g (20.05 mmol)of imidazole and 1.709 g (11.0 mmol) of tert-butyldimethylchlorosilanein 8.7 ml of abs. DMF is stirred at RT for 18 h under argon. After that,the reaction mixture is poured onto ice-water and the whole is extractedwith ethyl acetate. The organic phase is washed with cold 10% citricacid solution and saline. The combined aqueous phases are reextractedwith ethyl acetate. The combined organic phases are dried over sodiumsulfate and evaporated on a RE at approximately 30° C. The resultingproduct is dissolved in 28.8 ml of methanol and 11.2 ml of THF, and thissolution is treated, at RT, with 1.962 g of potassium carbonate in 11.2ml of water. After having been stirred for 2.25 h, the reaction mixtureis concentrated down to half its volume at approximately 30° C. and theresidue is treated with ethyl acetate and (cold) 10% citric acidsolution, and the phases are separated. The organic phase is washed afurther two times with saline. The combined aqueous phases arereextracted with ethyl acetate. The combined organic phases are driedover sodium sulfate and concentrated. The residue is purified by beingchromatographed twice on silica gel (hexane:ethyl acetate, 1:1 and then3:1), and the title compound is obtained. TLC R_(f) (hexane:ethylacetate. 1:1)=0.42. FAB-MS (M+H)⁺ =586. IR (KBr) inter alia: 1711, 1485,1260 and 1107 cm⁻¹. ¹ H-NMR (CD₃ OD) inter alia: 7.30-7.06 (m, 5H); 6.91and 6.65 (each d, each 1H); 6.00 and 5.41 (each d, in all 1 H from NH);3.75 (s, 3H); 2.21 and 2.12 (each s, each 3H); 1.31 and 1.21 (each s, inall 9H from Boc); 0.89 (s, 9H); 0.12 and 0.08 (each s, each 3H).

51f) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,3-dimethyl-4-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A mixture of 319.6 mg (0.546 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,3-dimethyl-4-methoxyphenyl)methyl!hexanoic acid, 232.5 mg (0.613mmol) of HBTU and 106.8 mg (0.613 mmol) ofH-(L)-Val-N-(2-methoxyethyl)amide (preparation, see Example 1b)) in 5.3ml of a 0.25 M solution of NMM in acetonitrile (2.4 equivalents) isstirred at RT for 2.25 h under argon. After that, the reaction mixtureis concentrated on a RE at approximately 30° C. and the residue is takenup in ethyl acetate; this solution is then washed, in succession, with10% citric acid, sat. sodium bicarbonate solution and saline (all beingcold). The combined aqueous phases are reextracted with ethyl acetate.The combined organic phases are dried over Na₂ SO₄ and concentrated. Thecrude product is chromatographed twice on silica gel (hexane:ethylacetate, 1:2 and 1:1), and the title compound is obtained. TLC R_(f)(hexane:ethyl acetate, 1:1)=0.16. FAB-MS (M+H)⁺ =742. HPLC t_(Ret)=22.41 min (gradient II). IR(CH₂ Cl₂)=inter alia 3434, 1701, 1667, 1499and 1165 cm⁻¹. ¹ H-NMR(CD₃ OD)=inter alia 7.3-7.1 (m, 5H); 6.85 and 6.64(each d, each 1H); 5.59 and 5.61 (each d, in all 1H from NH); 3.75 (s,3H); 2.16 and 2.02 (each s, each 3H); 1.31 and 1.20 (each s, in all 9Hfrom Boc); 0.95 (s, 9H); 0.68 and 0.66 (each d, each 3H); 0.17 and 0.16(each s, each 3H).

Example 52 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,4,5-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 44, the title compound is obtained from5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,4,5-trimethoxyphenyl)methyl!-hexanoyl-(L)-Val-N-(2-methoxyethyl)amidein abs. DMF using TBAF. The starting compound for the2,4,5-trimethoxybenzyl substituent can be bought from Fluka, Buchs,Switzerland, as 2,4,5-trimethoxybenzaldehyde, from which thecorresponding alcohol is obtained as an intermediate by reducing withsodium borohydride!.

Example 53 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,4,6-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 44, the title compound is obtained from5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,4,6-trimethoxyphenyl)methyl!-hexanoyl-(L)-Val-N-(2-methoxyethyl)amidein abs. DMF using MBAF. The starting compound for the2,4,6-trimethoxybenzyl substituent can be bought from Fluka, Buchs,Switzerland, as 2,4,6-trimethoxybenzaldehyde, from which thecorresponding alcohol is obtained as an intermediate by reducing withsodium borohydride!.

Example 54 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(5,6,7,8-tetrahydro-1-naphthyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 44, the title compound is obtained From5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(5,6,7,8-tetrahydro-1-naphthyl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amidein abs. DMF using TBAF. The starting compound for preparing thetetrahydronaphthyl substituent is obtained from tetralin bychloromethylation, see also, J. Org. Chem. 43, 2167(1978) for theinstructions!.

Example 55 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,5-dimethoxyphenyl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 44, the title compound is obtained from5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,5-dimethoxyphenyl)methyl!-hexanoyl-(L)-Val-N-(2-methoxyethyl)amide inabs. DMF using TBAF. The starting compound for the 2,5-dimethoxybenzylsubstituent can be bought from Fluka, Buchs, Switzerland as2,5-dimethoxybenzyl alcohol!.

Example 56 5(S)-Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,6-dimethoxyphenyl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 44, the title compound is obtained from5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,6-dimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide inabs. DMF using TBAF. The starting compound for the 2,6-dimethoxybenzylsubstituent, 2,6-dimethoxybenzyl alcohol, is prepared from methyl2,6-dimethoxybenzoate by reduction with lithium aluminium hydride inabs. THF. Methyl 2,6-dimethoxybenzoate is obtained from2,6-dimethoxybenzoic acid (Fluka, Buchs, Switzerland) by reaction withdimethyl sulfate in acetone and in the presence of potassium carbonate(see instructions in Chem. Letters, 1990, 389)!.

Example 57 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(4-methoxy-1-naphthyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 44, the title compound is obtained from5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(4-methoxy-1-naphthyl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amidein abs. DMF using TB AF. The starting compound for preparing thenaphthylmethyl substituent, 1-bromomethyl-4-methoxynaphthalene, isobtained from 1-methoxynaphthalene (Fluka, Buchs, Switzerland) bybrominating with I₂ /Br₂ in CHCl₃, reacting the resulting bromide bymeans of a Grignard reaction and working up with CO₂ to form thecorresponding acid; reaction of the latter with lithium aluminiumhydride to form 1-hydroxymethyl-4-methoxynaphthalene (reduction); andreaction of the latter with PBr₃, thereby yielding the desired startingmaterial (see Can. J. Chem. 59, 2629 (1981))!.

Example 58 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(4-cyano-1-naphthyl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 44, the title compound is obtained from5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(4-cyano-1-naphthyl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide inabs. DMF using TBAF. 1-Bromomethyl-4-cyanonaphthalene, the startingcompound for the 4-cyanonaphthylmethyl side chain, is obtained byFriedel-Crafts acylation of 1-bromonaphthalene (Fluka, Buchs,Switzerland), followed by hypochlorite oxidation of the resultingbromoacetophenone to give bromonaphthoic acid, whose reduction thenleads to the carbinol, from which the corresponding cyano compound isprepared using copper(I) cyanide, with the1-bromomethyl-4-cyanonaphthalene side chain precursor being obtainedfrom this cyano compound in the usual manner using PBr₃ (see Can. J.Chem. 59, 2629 (1981))!.

Example 59 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(4-fluoro-1-naphthyl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 44, the title compound is obtained from5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(4-fluoro-1-naphthyl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide inabs. DMF using TBAF. The starting compound for preparing the4-fluoronaphthylmethyl side chain, 1-bromomethyl-4-fluoronaphthalene, isprepared by reducing 4-fluoro-1-naphthoic acid (Aldrich, Steinheim, FRG)with lithium aluminium hydride followed by the reaction with PBr₃ (seeCan. J. Chem. 59, 2629 (1981))!.

Example 60 5(S)-(Boc-Amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A solution of 178 mg (0.204 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amidein 4 ml of abs. DMF is treated with 131 mg (0.408 mmol) of TBAF, and thereaction mixture is stirred at RT for 21 h. For the working up, thesolution is diluted with approximately 30 ml of ethyl acetate, and thewhole is washed, in succession, with water, sat. sodium bicarbonatesolution and saline. The combined aqueous phases are reextracted withethyl acetate. The combined organic phases are dried with sodium sulfateand concentrated. The residue is chromatographed on silica gel (ethylacetate). The product-containing fractions are combined, concentrated,dissolved once again in a little dioxane and lyophilized, with the titlecompound being obtained. IR(CH₂ Cl₂) inter alia: 3432, 1708, 1681, 1670,1495, 1167 and 1099 cm⁻¹. FAB-MS (M+H)⁺ =666. HPLC t_(Ret) =16.49 min(gradient II). ¹ H-NMR (CD₃ OD) inter alia: 6.80 and 6.63 (each d, each1H); 4.09 (d, 1H); 3.86 (s, 3H); 3.80 (2xs, 6H); 3.31 (s, 3H); 1.42 (s,9H); 0.90 (d, 6H).

The starting material is prepared as follows:

60a) 5(S)- 1(S)-(Boc-Amino)-2-cyclohexylethyl!dihydrofuran-2-(3H)-one

15 g (49.12 mmol) of 5(S)-1(S)-(Boc-amino)-2-phenylethyl!dihydrofuran-2-(3H)-one Example 2b)! aredissolved in 150 ml of methanol, and this solution is treated with 0.75g of Nishimura catalyst and hydrogenated (RT, standard pressure) untilthere is no further uptake of hydrogen. The catalyst is filtered off,the solvent is removed, and the residue is chromatographed on silica gel(toluene/ethyl acetate, 5:1). The title compound is obtained as a thick,viscous oil. IR (CH₂ Cl₂) inter alia: 3431, 1774, 1711, 1501 und 1170cm⁻¹. FAB-MS (M+1)⁺ =312. ¹ H-NMR (DMSO-d₆) inter alia: 6.80 (d, 1H);4.40 (m, 1H); 3.66 (m, 1H); 2.58-2.43 (m, 2H); 2.37 (dxq, 1H); 2.14 (m,1H) and 1.39 (s, 9H).

60b) 5(S)- 1(S)-(Boc-Amino)-2-cyclohexylethyl!-3(R)-(2,3,4-trimethoxyphenyl)-methyl!dihydrofuran-2-(3H)-one

A solution of 1.47 g (4.72 mmol) of 5(S)-1(S)-(Boc-amino)-2-cyclohexylethyl!dihydrofuran-2-(3H)-one in 6 ml ofabs. THF and 1 ml (1.65 equivalents) of DMPU is cooled down to -75° C.,under argon, and treated dropwise, at an internal temperature of below-70° C. and over the space of approximately 20 min, with 9.44 ml of a 1Msolution of lithium bis(trimethylsilyl)amide in THF (Aldrich). After afurther 20 min at -75° C., a solution of 1.45 g (4.72 mmol) of2,3,4-trimethoxybenzyl iodide Example 47b)! in 3 ml of abs. THF is addeddropwise to this mixture, within the space of approximately 10 min, andthis mixture is allowed to react at -75° C. for a further 2.5 h. For theworking up, the reaction mixture is treated with 1.76 ml of propionicacid, followed by 1.76 ml of water, and the temperature is allowed torise to 0° C. The reaction mixture is diluted with approximately 70 mlof ethyl acetate and stirred up with 30 ml of (cold) 10% citric acid.The aqueous phase is separated off and the organic phase is washed, insuccession, with saline, sat. sodium bicarbonate solution and withsaline once again. The combined aqueous phases are reextracted twicewith ethyl acetate. The combined organic phases are dried over sodiumsulfate and concentrated. The residue which remains after removing thesolvent is chromatographed on silica gel (toluene:ethyl acetate, 5:1).HPLC t_(Ret) =19.13 min (gradient II). FAB-MS (M+H)⁺ =491. IR(CH₂Cl₂)=inter alia 3429, 1766, 1711, 1602, 1495, 1165 und 1100 cm⁻¹. ¹H-NMR(CD₃ OD)=inter alia 6.86 (d, 1H); 6.70 (d, 1H); 4.37 (m, 1H); 3.87,3.82 and 3.81 (each s, each 3H); 3.37 (m, 1H); 3.13 (dxd, 1H); 2.94 (m,1H); 2.59 (dxd, 1H) and 1.40 (s, 9H).

60c) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(2,3,4-trimethoxyphenyl)-methyl!hexanoic acid

A solution of 600 mg (1.22 mmol) of 5(S)-1(S)-(Boc-amino)-2-cyclohexylethyl!-3(R)-(2,3,4-trimethoxyphenyl)methyl!dihydrofuran-2-(3H)-one in 20 ml ofdimethoxyethane and 9.9 ml of water is treated, at RT, with 4.9 ml of a1M solution of lithium hydroxide in water, and this reaction mixture isstirred for 2 h. It is then transferred to a separating funnel anddiluted with 60 ml of sat. ammonium chloride solution and 5 ml of a 10%citric acid solution (both being cold); this mixture is then extractedwith ethyl acetate and a little THF. The title compound, which is driedunder HV and subjected to further processing without being purified, isobtained after washing the organic phase with (cold) saline and dryingit over sodium sulfate. IR(CH₂ Cl₂) inter alia: 3431, 1710, 1602, 1495,1165 and 1100 cm⁻¹. FAB-MS (M+H)⁺ =510. HPLC t_(Ret) =16.13 min(gradient II).

60d)5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(2,3,4-trimethoxyphenyl)-methyl!hexanoic acid

A solution of 598 mg (1.175 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoic acid in 6 ml of DMF is treated,while being stirred, with 653 mg (9.4 mmol) of imidazole and 822 mg(5.287 mmol) of t-butyldimethylchlorosilane. After it has been stirredfor 17 h at RT, and under argon, the reaction solution is poured ontoice-water and the whole is extracted with ethyl acetate. The organicphase is washed with 10% citric acid solution and saline (cold). Thecombined aqueous phases are reextracted with ethyl acetate. The combinedorganic phases are dried with Na₂ SO₄ and evaporated. The crude productis dried under HV for approximately 2 h and, after that, is dissolved in15.6 ml of methanol and 5.3 ml of THF, and this solution is treated with941 mg of potassium carbonate in 5.3 ml of water. This reaction mixtureis stirred at RT for approximately 3 h, then concentrated down, atapproximately 30° C., to half the volume and diluted with ethyl acetate;the organic phase is washed with 10% citric acid and saline (both beingcold). The combined aqueous phases are reextracted with ethyl acetate.The combined organic phases are dried over Na₂ SO₄ and evaporated. Thecrude product is chromatographed on silica gel (hexane:ethyl acetate,2:1), and the title compound is obtained. IR(CH₂ Cl₂) inter alia: 3436,1708, 1603, 1494, 1166, 1100 and 837 cm⁻¹. FAB-MS (M+H)⁺ =624. HPLCt_(Ret) =23.14 min (gradient II). ¹ H-NMR (CD₃ OD) inter alia: 6.76 (d,1H); 6.59 (d, 1H); 6.07 and 5.50 (each d, in all 1H, rotamers of NH),3.86, 3.82 and 3.81 (each s, each 3H); 3.75-3.57 (m, 2H); 2.93-2.75 (m,2H); 2.70 (m, 1H); 1.42 (s, 9H); 0.87 (s, 6H); 0.11 and 0.08 (each s,each 3H).

60e)5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(2,3,4-trimethoxyphenyl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A mixture of 135 mg (0.265 mmol)5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoic acid, 100 mg (0.265 mmol) ofHBTU and 51 mg (0.291 mmol) of H-(L)-Val-N-(2-methoxyethyl)amidepreparation, see Example 1b)! in 2.5 ml of a 0.25 M solution of NMM inacetonitrile is stirred at RT for 21 h under argon. The solution isconcentrated down to half the volume on a RE at approximately 30° C. anddiluted with cold ethyl acetate; this solution is then washed, insuccession with 10% citric acid, water, sat. sodium bicarbonate solutionand saline. The title compound, which is subjected to further processingwithout being purified, is obtained after drying over sodium sulfate andremoving the solvent. IR (CH₂ Cl₂) inter alia: 3434, 1667, 1495, 1166,1097 and 838 cm⁻¹. FAB-MS (M+H)⁺ =780. HPLC t_(Ret) =24.79 min (gradientII). ¹ H-NMR (CD₃ OD) inter alia: 6.80 and 6.64 (each d, each 1H); 5.85(d, 1H); 3.88, 3.83 and 3.81 (each s, each 3H); 3.32 (s, 3H); 1.43 (s,9H); 0.90 (s, 9H); 0.13 (d, 6H).

Example 61 5(S)-(Boc-Amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)-methyl!hexanoyl-(L)-Ala-N-(2-methoxyethyl)amide

In analogy with Example 1), 115 mg (0.17 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Ala-N-(2-methoxyethyl)amide in 5 mlof DMF are desilylated with 114 mg (0.36 mmol) of TBAF and worked up.Column chromatography (SiO₂, ethyl acetate/hexane, 2:1→3:1→100% ethylacetate) affords the title compound: TLC R_(f) (A)=0.42; t_(Ret)(II)=15.4 min; FAB-MS (M+H)⁺ =578.

The starting material is prepared as follows:

61a) Z-(L)-Ala-N-(2-methoxyethyl)amide

Under protective gas, an ice-cold solution of 5.0 g (28.5 mmol) ofZ-(L)-alanine in 125 ml of methylene chloride is activated with 6.48 g(31.4 mmol) of DCC and 4.24 g(31.4 mmol) of HOBT. 2.45 ml (28.5 mmol) of2-methoxyethylamine (Fluka, Buchs, Switzerland) are subsequently addeddropwise to the resulting suspension, and this reaction mixture isthoroughly stirred at RT for 60 h. It is then filtered and the filtrateis washed with sat. NaHCO₃ solution and saline, dried with Na₂ SO₄ andevaporated. Digesting the crude product with DIPE and medium pressurechromatography (®LiChroprep Si 60; silica gel for medium pressurechromatography; Merck, Darmstadt, FRG), loading as a solution inmethylene chloride/methanol; eluting with methylene chloride→methylenechloride/methanol 19:1→92:8)! affords the title compound: TLC R_(f)(B)=0.56; t_(Ret) (II)=9.5 min.

61b) H-(L)-Ala-N-(2-methoxyethyl)amide

Hydrogenating 4.6 g (16.4 mmol) of Z-(L)-Ala-N-(2-methoxyethyl)amide in100 ml of methanol, at RT under low pressure and in the presence of 1 gof 10% Pd/C, affords the title compound after filtering off thecatalyst, evaporating the filtrate and filtering a solution of the crudeproduct in methylene chloride through silica gel with 10% methanol inmethylene chloride: FAB-MS (M+H)⁺ =147; ¹ H-NMR (200 MHz, CD₃ OD): 1.25(d, J=7 Hz, H₃ C), 3.33 (s, H₃ C--O), 3.3-3.5 (m, HC.sup.α, H₂ C--CH₂).

61c)5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Ala-N-(2-methoxyethyl)amide

Under an N₂ atmosphere, 150 mg (0.27 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoic acid (Example 12d)! and 42.8 mg (0.29mmol) of H-(L)-Ala-N-(2-methoxyethyl)amide are dissolved in 2.6 ml of0.25 M NMM/CH₃ CN, and this solution is treated with 111 mg (0.29 mmol)of HBTU. Since HPLC indicates that starting material is still presentafter 18 h at RT, a further 1.1 equivalents of HBTU are added. After atotal of 48 h, the reaction mixture is evaporated and the residue istaken up in ethyl acetate; this solution is washed with water, 2portions of 10% citric acid solution, water, 2 portions of sat. NaHCO₃solution and, finally, saline. The inorganic phases are extracted afurther 2× with ethyl acetate, and the organic phases are dried with Na₂SO₄ and evaporated. Column chromatography (SiO₂, hexane/ethyl acetate,2:1→1:1) yields the title compound: TLC R_(f) (C)=0.14; t_(Ret)(II)=22.6 min.

Example 62 5(S)-(Boc-Amino)-4(S)-hydroxy-6-p-(2-methoxyethoxy)phenyl!-2(R)-(p-benzyloxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

1.21 g (1.41 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-p-(2-methoxyethoxy)phenyl!-2(R)-(p-benzyloxyphenyl)methyl!-hexanoyl-(L)-Val-N-(2-methoxyethyl)amide(Example 62f)) in 31 ml of DMF are desilylated with 890 mg (2.82 mmol)of TBAF under an N₂ atmosphere. After 18 h at RT, the mixture is pouredonto 430 ml of water and the whole is extracted with 3 portions of ethylacetate/methanol, ˜10:1. The organic phases are washed 2 times with sat.NaHCO₃ solution and with saline, dried with Na₂ SO₄ and evaporated togive the title compound: TLC R_(f) (F)=0.38; t_(Ret) (II)=16.4 min;FAB-MS (M+H)⁺ =750.

The starting material is prepared as follows:

62a) 5(S)-1(S)-(Boc-Amino)-2-(p-hydroxyphenyl)ethyl!-dihydrofuran-2-(3H)-one

Hydrogenating 3.0 g (7.29 mmol) of 5(S)-1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)-ethyl!dihydrofuran-2-(3H)-onepreparation, see Example 1g)! in 100 ml of methanol with 0.6 g of 10%Pd/C results in the title compound, after filtering off the catalyst andevaporating the filtrate: t_(Ret) (II)=10.6 min.

62b) 5(S)- 1(S)-(Boc-Amino)-2-p-(2-methoxyethoxy)phenyl!ethyl!dihydrofuran-2-(3H)-one

3.17 g (9.86 mmol) of 5(S)-1(S)-(Boc-amino)-2-(p-hydroxyphenyl)ethyl!dihydrofuran-2-(3H)-one in 190ml of DMF/dioxane, 1: 1, are treated, under an N₂ atmosphere, with 6.4 g(19.7 mmol) of Cs₂ CO₃ and 2.0 g (9.86 mmol) of 2-methoxyethyl iodide.Since HPLC indicates that uureacted 5(S)-1(S)-(Boc-amino)-2-(p-hydroxyphenyl)ethyl!-dihydrofuran-2-(3H)-one isstill present after 18 h at RT, a further 1.2 g of 2-methoxyethyl iodideare added in portions. As soon as HPLC indicates that the reaction iscomplete, the reaction mixture is poured onto 190 ml of ice-water, andthe whole is extracted 3× with methylene chloride. The organic phasesare washed with water and saline, dried with Na₂ SO₄ and evaporated.Stirring up the residue with hexane in an ultrasonication bath affordsthe title compound: TLC R_(f) (D)=0.08; FAB-MS (M+H)⁺ =380.

62b') 2-Methoxyethyl iodide

A solution of 10 ml (109 mmol) of 2-chloroethyl methyl ether in 205 mlof acetone is treated in portions with 80.1 g (534 mmol) of NaI, and themixture is boiled under reflux for 20 h. Partitioning the reactionmixture between 2 portions of ether and saline, drying the organicphases with Na₂ SO₄ and evaporating them (RT, 300 mbar) affords thetitle compound: ¹ H-NMR (200 MHz, CDCl₃): 3.25 (t, J=7 Hz, 2H), 3.39 (s,3H), 3.65 (t, J=7Hz,2H).

62c) 5(S)- 1(S)-(Boc-Amino)-2- p-(2-methoxyethoxy)phenyl!ethyl!-3(R)-(p-benzyloxyphenyl)methyl!dihydrofuran-2-(3H)-one

Under an N₂ atmosphere, 3.6 g (9.48 mmol) of 5(S)- 1(S)-(Boc-amino)-2-p-(2-methoxyethoxy)phenyl!ethyl!dihydrofuran-2-(3H)-one, dissolved in17.3 ml of THF and 1.9 ml of DMPU, are deprotonated, at -70° C., with18.58 ml of a 1 M solution of lithium bis(trimethylsilyl)amide in THF,and, after 15 min, alkylated with 3.07 g (9.48 mmol) ofp-benzyloxybenzyl iodide (Example 1d)) in 6 ml of THF. After 30 min at-75° C., the mixture is protonated with 3.53 ml (47.4 mmol) of propionicacid and 3.53 ml of water and warmed to 0° C. The reaction mixture isdiluted with 95 ml of ethyl acetate and the whole is washed with 10%citric acid solution, sat. NaHCO₃ solution and saline. The aqueousphases are extracted with 2 portions of ethyl acetate. The organicphases are dried with Na₂ SO₄ and evaporated. Column chromatography(SiO₂, hexane/ethyl acetate, 1:1) and crystallization from ethylacetate/hexane yields the pure title compound: TLC R_(f) (C)=0.38;t_(Ret) (II)=18.0 min; FAB-MS (M+H)⁺ =576.

62d) 5(S)-(Boc-Amino)-4(S)-hydroxy-6- p-(2-methoxyethoxy)phenyl!-2(R)-(p-benzyloxyphenyl)methyl!hexanoic acid

3.85 g (6.68 mmol) of 5(S)- 1(S)-(Boc-amino)-2-p-(2-methoxyethoxy)phenyl!ethyl!-3(R)-(p-benzyloxyphenyl)methyl!dihydrofuran-2-(3H)-one in 107 ml ofdimethoxyethane and 54 ml of water are hydrolysed, under a protectivegas, with 26.5 ml of a 1 M lithium hydroxide solution. After 17 h at RT,the reaction mixture is treated with an ice-cold mixture of 324 ml ofsat. NH₄ Cl solution, 27 ml of 10% citric acid solution and 134 ml ofmethylene chloride. Methanol is added in order to dissolve the productcompletely. The aqueous phase is separated off and extracted 2× withmethylene chloride. The organic phases are washed with saline, driedwith Na₂ SO₄ and evaporated: t_(Ret) (I)=15.8 min; FAB-MS (M+H)⁺ =594.

62e) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-p-(2-methoxyethoxy)phenyl!-2(R)- (p-benzyloxyphenyl)methyl!hexanoic acid

3.85 g (6.48 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-p-(2-methoxyethoxy)-phenyl!-2(R)- (p-benzyloxyphenyl)methyl!hexanoicacid in 11 ml of DMF are silylated, at RT for 16 h and under aprotective gas, with 4.49 g (29.8 mmol) oftert-butyldimethylchlorosilane and 3.6 g (53.1 mmol) of imidazole. Thereaction mixture is poured onto ice-water and the whole is extracted 3times with ethyl acetate. The organic phases are washed with 10% citricacid solution, 2 times with water and with saline, dried with Na₂ SO₄and evaporated. The residue is dissolved in 79 ml of methanol and 30 mlof THF, and this solution is treated with 5.37 g of potassium carbonateand 30 ml of water and stirred at RT for 3 h. The reaction mixture issubsequently poured onto an ice-cold 10% citric acid solution, and thismixture is extracted 3 times with ethyl acetate. The organic phases arewashed with 2 portions of H₂ O and saline, dried with Na₂ SO₄ andevaporated. Column chromatography (SiO₂, hexane/ethyl acetate, 1:1)affords the title compound: TLC R_(f) (C)=0.28; t_(Ret) (II)=20.9 min.

62f) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-p-(2-methoxyethoxy) -phenyl!-2(R)-(p-benzyloxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

1.00 g (1.41 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-p-(2-methoxyethoxy)phenyl!-2(R)- (p-benzyloxyphenyl)methyl!hexanoic acidand 270 mg (1.55 mmol) of H-(L)-Val-N-(2-methoxyethyl)amide (Example1b)) in 13.5 ml of 0.25 M NMM/Cl₃ CN are reacted, under a protectivegas, with 588 mg (1.55 mmol) of HBTU. After 18 h at RT, the mixture isfinally evaporated. The residue is taken up in ethyl acetate, and thesolution is washed with water, 2× with 10% citric acid solution, water,2× with sat. NaHCO₃ solution, 1× with water and 1× with saline. Theaqueous phases are extracted a further 2× with ethyl acetate, and theorganic phases are dried with sodium sulfate and evaporated. The titlecompound is obtained: t_(Ret) (II)=22.7 min; FAB-MS (M+H)⁺ =864.

Example 63 5(S)-(Boc-Amino)-4(S)-hydroxy-6-p-(2-methoxyethoxy)phenyl!-2(R)-(p-hydroxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

Hydrogenating a solution of 600 mg (0.80 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6- p-(2-methoxyethoxy)phenyl!-2(R)-(p-benzyloxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide(Example 62) in 20 ml of methanol in the presence of 200 mg of 10% Pd/C,filtering the mixture and evaporating it, results in the title compound:TLC R_(f) (F)=0.19; t_(Ret) (II)=12.3 min; FAB-MS (M+H)⁺ =660.

Example 64 5(S)-(Boc-Amino)-4(S)-hydroxy-6-p-(2-methoxyethoxy)phenyl!-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

Under an N₂ atmosphere, 100 mg (0.152 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6- p-(2-methoxyethoxy)phenyl!-2(R)-(p-hydroxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide(Example 63) in 3 ml of DMF/dioxane, 1:1, are treated, at 0° C., with98.7 mg (0.303 mmol) of Cs₂ CO₃ and 9.4 g (0.152 mmol) of methyl iodide,and the mixture is stirred at RT for 24 h. Since HPLC indicates that thestarting material is still present, a further 6 μl of methyl iodide areadded. After a further 20 h at RT, the reaction mixture is poured ontowater and the whole is extracted with 3 portions of methylene chloride.The organic phases are washed with water and saline, dried with Na₂ SO₄and evaporated. Recrystallizing from methylene chloride, a littlemethanol and DIPE yields the title compound: TLC R_(f) (H)=0.47; t_(Ret)(II)=14.0 min; FAB-MS (M+H)⁺ =674.

Example 65 5(S)-(Boc-Amino)-4(S)-hydroxy-6-p-(2-methoxyethoxy)phenyl!-2(R)-{p-(2-methoxyphenyl)ohenyl!methyl}-hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

Under an N₂ atmosphere, 100 mg (0.152 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6- p-(2-methoxyethoxy)phenyl!-2(R)-(p-hydroxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide(Example 63) in 3 ml of DMF/dioxane, 1:1, are treated, at 0° C., with98.7 mg (0.303 mmol) of Cs₂ CO₃ and 40 mg (0.152 mmol) of 2-methoxyethyliodide (Example 62b'), and the mixture is stirred at RT for 24 h. SinceHPLC indicates that starting material is still present, a further 60 mgof 2-methoxyethyl iodide are added in 3 portions, with the mixture beingstirred at RT for a few hours on each occasion. Precipitating out of thereaction mixture with 4 ml of ice-water, filtering, columnchromatography (SiO₂, methylene chloride/THF, 3:1), and digesting inhexane, yields the pure title compound: TLC R_(f) (H)=0.59; t_(Ret)(II)=13.9 min; FAB-MS (M+H)⁺ =718.

Example 66 5(S)-(Boc-Amino)-4(S)-hydroxy-6-p-(2-methoxyethoxy)phenyl!-2(R)-{p-methoxyphenyl)phenyl!methyl}-hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 1, 3.7 g (4.84 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-4-{2-(methoxy)ethoxy}phenylmethyl!-hexanoyl-(L)-Val-N-(2-methoxyethyl)amide(Example 66f)) in 15 ml of DMF are reacted with 3.09 g (9.78 mmol) ofTBAF trihydrate to give the title compound. The reaction mixture ispoured onto water and the whole is extracted with 4 portions of ethylacetate. The organic phases are washed with sat. NaHCO₃ solution, waterand saline, dried with Na₂ SO₄ and evaporated. The pure title compoundis finally obtained after stirring up with diethyl ether and filtering.TLC R_(f) (A)=0.4; t_(Ret) (II)=15.97 min; FAB-MS (M+H⁺)=650.

The starting compound is prepared in the following manner:

66a) 3(R)- (4-Benzyloxyphenyl)methyl!-5(S)-1(S)-(Boc-amino)-2-cyclohexylethyl!-dihydrofuran-2-one

In analogy with Example 1h), 5.2 g (16.7 mmol) of 5(S)-1(S)-(Boc-amino)-2-cyclohexylethyl!dihydrofuran-2-one (Example 12a)),dissolved in 50 ml of THF, are deprotonated, at -70° C., with 33.4 ml ofa 1M solution of lithium is(trimethylsilyl)amide in THF, and alkylated(at -75° C. for 1 h) with 5.2 g (16.07 mmol) of p-benzyloxybenzyl iodidepreparation, see Example 1d)! in 15 ml of THF. Adding 6.2 ml (83.02mmol) of propionic acid and water at -75° C., and further working up,affords the title compound after column chromatography (SiO₂,hexane/ethyl acetate: 4:1). TLC R_(f) (hexane/ethyl acetate: 4:1)=0.27;t_(Ret) (II)=20.41 min.

66b) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(4-benzyloxyphenyl)-methyl!hexanoic acid

2.4 g (4.728 mmol) of 3(R)- (4-benzyloxyphenyl)-methyl!-5(S)-1(S)-(Boc-amino)-2-cyclohexylethyl!dihydrofuran-2-one in 10 ml ofdimethoxyethane are hydrolysed, under a protective gas, with 9.45 ml ofa 1M lithium hydroxide solution. After 17 h at RT, the reaction mixtureis treated with an ice-cold mixture of 324 ml of sat. NH₄ Cl solution,27 ml of 10% citric acid solution and 134 ml of methylene chloride.Methanol is added to dissolve the product completely. The aqueous phaseis separated off and extracted 2× with methylene chloride. The organicphases are washed with saline, dried with Na₂ SO₄ and evaporated. Thecrude product is purified by column chromatography (SiO₂, eluent C),with the title compound being obtained. TLC R_(f) (C)=0.35; t_(Ret)(II)=17.88 min FAB-MS (M+H⁺)=526.

66c)5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(4-benzyloxyphenyl)methyl!hexanoic acid

In analogy with Example 1j), 28.8 g (54.8 mmol) of5(S)-(Boc-amino)4(S)-hydroxy-6-cyclohexyl-2(R)-(4-benzyloxyphenyl)methyl!hexanoic acid in 288 ml of DMF, are convertedinto the title compound with 35.8 g (237.6 mmol) oftert-butyldimethylchlorosilane and 30 g (440 mmol) of imidazole. Thetitle compound is purified by column chromatography (SiO₂, hexane/ethylacetate: 4:1 to 1:1); TLC R_(f) (E)=0.34; t_(Ret) (gradient from 75 to100% (a) in (b) over 20 min)=25.06 min; FAB-MS (M+H⁺)=526.

66d)5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(4-benzyloxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A solution of 3 g (18.7 mmol) of H-(L)-Val-N-(2-methoxy-ethyl)amide and10 g (15.6 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(4-benzyloxyphenyl)methyl!hexanoic acid in 50 ml of DMF is cooled downto 5° C. in an ice bath and treated with 2.9 ml (17.2 ml) of diethylcyanophosphonate (Aldrich, Milwaukee, USA) and, after that, with 5.5 mlof triethylamine. After the mixture has been stirred at RT, it is pouredonto water and the whole is extracted 3 times with ethyl acetate. Thecombined organic phases are washed with water, saturated sodiumbicarbonate solution (twice) and saline, and, after having been driedover sodium sulfate, concentrated under reduced pressure. The titlecompound is purified by column chromatography (SiO₂, eluent C); TLCR_(f) (A)=0.56; t_(Ret) (B)=24.82 min. FAB-MS (M+H⁺)=796.

66e)5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(4-hydroxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxythyl)amide

0.64 g (0.804 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(4-benzyloxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in 20ml of methanol is hydrogenated in the presence of 0.32 g of 10% Pd/C.The title compound, which is obtained after filtering off the catalystand evaporating the filtrate, is subjected to further reaction withoutany additional purification; TLC R_(f) (C)=0.18; t_(Ret) (II)=21.81 min;FAB-MS (M+H⁺)=706.

66f)5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(4-{2-(methoxy)ethoxy}phenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A solution of 0.75 g (1.06 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(4-hydroxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in 10ml of dioxane is treated with 1.384 g (4.25 mmol) of caesium carbonateand, after 4 h, with 0.79 g (4.25 mmol) of 2-methoxyethyl iodide(Example 62b')). After having been stirred at 80° C. for 24 h, thereaction mixture is poured onto water and ethyl acetate. After theorganic phase has been separated off, the aqueous solution is washed afurther 3 times with ethyl acetate. The combined extracts are washed, insuccession, with water, saturated aqueous sodium bicarbonate solutionand saline. After drying over sodium sulfate and evaporating underreduced pressure, the resulting residue is stirred up with hexane andfiltered off. Column chromatography (SiO₂, hexane/acetone: 2:1) yieldsthe pure title compound. TLC R_(f) (C)=0.2; t_(Ret) (II)=21.9 min;FAB-MS (M+H⁺)=764.

Example 675(S)-(2,2,2-Trifluoroethoxycarbonylamino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(4-{2-(methoxy)ethoxy}phenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

500 mg (0.909 mmol) of 5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R)-(4-{2-(methoxy)ethoxy}-phenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amidein 5 ml of DMF are treated, at 0° C. and in succession, with 0.51 ml(3.65 mmol) of triethylamine and 0.34 g (2.09 mmol) of trifluoroethylchloroformate (U.S. Pat. No. 3,852,464). After having been stirred for10 min, the reaction mixture is poured onto water and the whole isextracted 3× with ethyl acetate. The combined extracts are washed, insuccession, with aqueous, saturated sodium bicarbonate solution andsaline, and, after having been dried over sodium sulfate, concentratedunder reduced pressure. The title compound is obtained from the residueby treating it with ethyl acetate. TLC R_(f) (B)=0.77; t_(Ret)(II)=15.26 min; FAB-MS (M+H⁺)=676.

The starting compound is prepared in the following manner:

67a) 5(S)-Amino-4(S)-hydroxy-6-cyclohexyl-2(R)-(4-{2-(methoxy)ethoxy}phenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

2.3 g (3.54 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(4-{2-(methoxy)ethoxy}phenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide(Example 66) in 25 ml of methylene chloride are treated, at 0° C., with25 ml of trifluoroacetic acid. After having been stirred at RT for 2 h,the reaction mixture is evaporated and the residue is partitionedbetween saturated, aqueous sodium bicarbonate solution and ethylacetate. The organic phase is washed once again with saturated, aqueoussodium bicarbonate solution and saline, and evaporated to dryness. Thedry residue is digested in 100 ml of diethyl ether in an ultrasonicationbath, after which it is filtered off with suction and washed. The titlecompound is obtained by drying the filter residue at RT under highvacuum: TLC R_(f) (B)=0.4; t_(Ret) (II)=10.2 min; FAB-MS (M+H⁺)=550.

Example 68 5(S)-(Boc-Amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(3,4-methylenedioxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 60, the title compound is obtained from5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(3,4-methylenedioxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amideusing TBAF in abs. DMF.

Example 69 5(S)-(Boc-Amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(3,4-methylenedioxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 60, the title compound is obtained from5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(3,4-dimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amideusing TBAF in abs. DMF.

Example 70 5(S)-(Boc-Amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(3-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 60, the title compound is obtained from5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(3-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide usingTBAF in abs. DMF.

Example 71 5(S)-(Boc-Amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(3,4,5-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 60, the title compound is obtained from5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(3,4,5-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amideusing TBAF in abs. DMF.

Example 72 5(S)-(Boc-Amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(2,4-dimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 60, the title compound is obtained from5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(2,4-dimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amideusing TBAF in abs. DMF.

Example 73 5(S)-(Boc-Amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(2-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 60, the title compound is obtained from5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(2-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide usingTBAF in abs. THF.

Example 74 5(S)-(Boc-Amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(2,3-dimethyl-4-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 60, the title compound is obtained from5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(2,3-dimethyl-4-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amideusing TBAF in abs. DMF.

Example 75 5(S)-(Boc-Amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(2,4,5-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 60, the title compound is obtained from5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(2,4,5-tximethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyleamideusing TBAF in abs. THF.

Example 76 5(S)-(Boc-Amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(2,4,6-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 60, the title compound is obtained from5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(2,4,6-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amideusing TBAF in abs. DMF.

Example 77 5(S)-(Boc-Amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(5,6,7,8-tetrahydro-1-methyl)naphthyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 60, the title compound is obtained from5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(5,6,7,8-tetahydro-1-methyl)naphthyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amideusing TBAF in abs. DMF.

Example 78 5(S)-(Boc-Amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(2,5-dimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 60, the title compound is obtained from5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(2,5-dimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amideusing TBAF in abs. DMF.

Example 79 5(S)-(Boc-Amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(2,6-dimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 60, the title compound is obtained from 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(2,6-dimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amideusing TBAF in abs. DMF.

Example 80 5(S)-(Boc-Amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(4-methoxy-1-naphthyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 60, the title compound is obtained from5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(4-methoxy-1-naphthyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amideusing TBAF in abs. DMF.

Example 81 5(S)-(Boc-Amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(4-cyano-1-naphthyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 60, the title compound is obtained from5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(4-cyano-1-naphthyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amideusing TBAF in abs. DMF.

Example 82 5(S)-(Boc-Amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(4-fluoro-1-naphthyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 60, the title compound is obtained from5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(4-fluoro-1-naphthyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amideusing TBAF in abs. DMF.

Example 835(S)-(3-Hydroxy-2-methylphenylcarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

150 mg (0.251 mmol) of 5(S)-amino-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide(hydrochloride salt) are dissolved in dichloromethane, and the organicphase is washed with sat. sodium bicarbonate solution, dried over sodiumsulfate and concentrated. The amine which has been liberated is stirred,at RT for 16 h, in 2.36 ml of a (0.25 M) solution of NMM in acetonitriletogether with 105 mg of HBTU (1.1 equivalents) and 42 mg (1.1equivalents) of 3-hydroxy-2-methylbenzoic acid prepared in accordancewith F. Fringuelli, V. Mancini and A. Taticchi, Tetrahedron 25, 4249(1969)!. The reaction mixture is taken up in a cold ethyl acetate/THFmixture, and the whole is washed, in succession, with 10% citric acid,water, sat. sodium bicarbonate solution and saline. After the mixturehas been dried over sodium sulfate, the solvent is removed and theresidue is digested twice with diethyl ether. The solid precipitate isfiltered off with suction, washed with diethyl ether and dried,resulting in the title compound: FAB-MS (M+H)⁺ =694; t_(Ret) (II)=9.08min.

The starting material is prepared as follows:

83a) 5(S)-Amino-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!-hexanoyl-(L)-Val-N-(2-methoxyethyl)amide(hydrochloride salt)

1.5 g (2.27 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide(Ex. 47) is added, under argon and in portions, to 10 ml of ice-cooled 4N hydrogen chloride in dioxane, and the mixture is stirred for 3.5 hwhile being cooled with ice. The reaction solution is briefly evacuatedin order to remove the excess hydrogen chloride and then frozen andlyophilized. The lyophilisate is stirred up for a further 1 h in acetoneand then filtered off with suction, washed with hexane and dried,thereby yielding the title compound: FAB-MS (M+H)⁺ =560; t_(Ret)(II)=7.30 min.

Example 845(S)-(2-Methoxy-1(R,S)-methylethoxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

1 g (1.84 mmol) of 5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amideprepared in accordance with Example 22a)! in 30 ml of THF is cooled downto approximately 7° C. using ice-water, and treated with 0.909 ml (3.5equivalents) of triethylamine followed by 563 mg (2 equivalents) of2-methoxy-1(R,S)-methylethyl chloroformate. The cooling bath is removedand the mixture is subsequently stirred at RT for a further 1 h. Thereaction mixture is poured onto water and the whole is extracted withethyl acetate. The organic phase is washed, in succession, with water,sat. sodium bicarbonate solution, water and saline. After drying oversodium sulfate, and removing the solvent, the residue is digested withether, the precipitate is filtered off and dried and the title compoundthus obtained: FAB-MS (M+H)⁺ =622; t_(Ret) (I)-14.55 and 14.70 min(diastereomeric mixture).

The starting material is prepared in the following manner:

84a) 2-Methoxy-1(R,S)-methylethyl chloroformate

1 ml (10.2 mmol) of 1-methoxy-2-propanol (Fluka, Buchs, Switzerland) isinjected slowly into an ice-cold solution of 916 mg (1.1 equivalent) ofbis(trichloromethyl) carbonate (triphosgene; Fluka, Buchs, Switzerland)in 35 ml of ether using a syringe. At the same time, 1 ml (1.2equivalents) of pyridine in 5 ml of ether is added dropwise from adropping funnel. After the addition has ended, the mixture is left tostir at RT for a further 60 min. The reaction mixture is filteredthrough wadding and the solvent is carefully evaporated off (35° C.waterbath). The oily residue (title compound) is subjected to furtherprocessing without any purification. ¹ H-NMR (200 MHz; CDCl₃)=inter alia5.05/m (1H); 3.30/s (3H); 1.27/d (3H).

Example 85 5(S)-(Boc-Amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-(cyclohexyl)Gly!-N-(2-methoxyethyl)amide

In analogy with Example 12, the title compound is obtained from5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-(cyclohexyl)Gly!-N-(2-methoxyethyl)amide using TBAF in DMF. FAB-MS(M+H)⁺ =646; t_(Ret) (I)=17.46 min.

The starting material is prepared as follows:

85a)5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-(cyclohexyl)Gly!-N-(2-methoxyethyl)amide

In analogy with Example 12e), the title compound is obtained from 1.128g (2 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoic acid prepared in accordance withExample 12d)!, 472 mg (1.1 equivalents) of H-(L)-(cyclohexyl)Gly!-N-(2-methoxyethyl)amide prepared in accordance withExample 20c)!, 0.36 ml (1.1 equivalents) of diethyl cyanophosphonate(Aldrich, Milwaukee/USA) and 0.7 ml (2.5 equivalents) of triethylaminein 10 ml of DMF. FAB-MS (M+H)⁺ =760; t_(Ret) (I)=24.73 min.

Example 865(S)-(Ethoxycarbonyl-(L)-Val-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl) amide

In analogy with Example 27, the title compound is obtained as acolourless solid, after digesting with ether, by proceeding from 1 g(1.844 mmol) of 5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!-hexanoyl-(L)-Val-N-(2-methoxyethyl)amideprepared in accordance with Example 22a)!, 500 mg (1.4 equivalents) ofethoxycarbonyl-(L)-valine, 0.43 ml (1.5 equivalents) of diethylcyanophosphonate and 1.34 ml (9.61 mmol) of triethylamine in 40 ml ofDMF. FAB-MS (M+H)⁺ =677; t_(Ret) (I)=14.68 min.

The starting material is prepared in the following manner:

86a) N-(Ethoxycarbonyl)-(L)-valine

The title compound is prepared, in analogy with Example 30a), fromL-valine in 2N NaOH and dioxane using ethyl chloroformate (Fluka, Buchs,Switzerland), and subjected to further processing without purification.

Example 875(S)-(1,1-Dimethyl-2-methoxycarbonylamino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In analogy with Example 26, the title compound is obtained from 813 mg(1.5 mmol) of 5(S)-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-methoxyphenyl)methyl!-hexanoyl-(L)-Val-N-(2-methoxyethyl)amideprepared in accordance with Example 22a)!, 490 mg (2 equivalents) of(1,1-dimethyl-2-methoxy)ethyl chloroformate and 0.6 ml (2.9 equivalents)of triethylamine. Purification is effected by chromatography on silicagel (eluent: hexane/acetone, 2:1). FAB-MS (M+H)⁺ =636; t_(Ret) (I)=15.45min.

The starting material is prepared as follows:

87a) 1-Methoxy-2-methyl-2-propanol

10.8 g (0.1 mol) of 1-chloro-2-methyl-2-propanol (Lancaster Synthesis,Bischheim, France) in 30 ml of methanol is treated, under argon, with20.4 ml of a solution of sodium methoxide (110 mmol; 1.1 equivalents) inmethanol, and the mixture is boiled under reflux for 2.5 h. After thereaction has ended, the precipitate is filtered off and the solvent isdistilled off via a Vigreux column, and the residue is distilled atstandard pressure, yielding the title compound: ¹ H-NMR (200 MHz;CDCl₃)=3.33/s (3H); 3.15/s (2H); 1.13/s (6H). FAB-MS (M+H)⁺ =105. see,also Amer., Soc. 75, 155 (1953)!.

87b) (1,1-Dimethyl-2-methoxy)ethyl chloroformate

770 mg (2.59 mmol) of bis(trichloromethyl) carbonate (triphosgene;Fluka, Buchs, Switzerland) is dissolved, at RT, in 25 ml of ether, andthis solution is treated with 737 mg (7.07 mmol) of1-methoxy-2-methyl-2-propanol dissolved in a little ether. The solutionis cooled in an ice bath and slowly treated with 0.67 ml (8.48 mmol) ofpyridine in 3 ml of ether. After the addition has ended, the ice bath isremoved and the mixture is subsequently stirred at RT for 1 h. Thereaction mixture is filtered through wading and the solvent is distilledoff at RT. The crude product (title compound) is subjected to furtherprocessing without purification. IR (CH₂ Cl₂): inter alia: 1780, 1210,1198, 1145 and 1120 cm⁻¹.

Example 88 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(4-biphenylyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl) amide

0.21 g (0.276 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(4-biphenylyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl) amide in 4 mlof DMF is desilylated, under an N₂ atmosphere, with 0.174 g (0.55 mmol)of TBAF. After 18 h at RT, the reaction mixture is poured onto water andthe whole is extracted with 3 portions of ethyl acetate. The organicphases are washed with sat. NaHCO₃ solution and saline, dried with Na₂SO₄ and evaporated. Stirring up in DIPE affords the title compound: TLCR_(f) (B)=0.55; t_(Ret) (II)=16.5 min; FAB-MS (M+H)⁺ =646.

The starting material is prepared in the following manner:

88a) 5(S)- 1(S)-(Boc-Amino)-2-phenylethyl!-3(R)-(4-biphenyl)methyl!dihydrofuran-2-(3H)-one

In analogy with Example 5d), 5.0 g (16.37 mmol) of 5(S)-1(S)-(Boc-amino)-2-phenylethyl!dihydrofuran-2-(3H)-one dissolved in 24ml of THF and 2.8 ml of DMPU are deprotonated, at -70° C., with 32.7 mlof a 1 M solution of lithium bis(trimethylsilyl)amide in THF, andalkylated (from -75° C. to -50° C.) with 6.07 g (24.6 mmol) of4-biphenylylmethyl bromide (Salor; Milwaukee/USA) in 20 ml of THF.Protonating with 6.1 ml (81.9 mmol) of propionic acid and 6.1 ml ofwater, at -75° C., extracting and medium pressure chromatography(gradient: 0-1% ethyl acetate in toluene) affords the title compound:TLC R_(f) (D)=0.57; t_(Ret) (II)=18.8 min.

88b) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(4-biphenylyl)methyl!hexanoic acid

1.3 g (2.76 mmol) of 5(S)- 1(S)-(Boc-amino)-2-phenylethyl!-3(R)-(4-biphenylyl)methyl!-dihydrofuran-2-(3H)-one are hydrolysed, in 28 mlof dimethoxyethane, with 11 ml of a 1 M solution of lithium hydroxide inwater. After 16 h at RT, the dimethoxyethane is evaporated off on a REand the residue is treated with an ice-cold mixture of 15 ml of sat. NH₄Cl solution, 80 ml of 10% citric acid solution and methylene chloride.The aqueous phase is separated off and extracted 2× with methylenechloride. The organic phases are washed with saline, dried with Na₂ SO₄and evaporated to give the title compound: TLC R_(f) (B)=0.4; t_(Ret)(II)=16.4 min.

88c) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(4-biphenylyl)methyl!hexanoic acid

Under a protective gas, 1.23 g (2.51 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl)-2(R)-(4-biphenylyl)methyl!hexanoic acid in 25 ml of DMF are silylated, at RTand for 20 h, with 1.74 g (11.5 mmol) of tert-butyldimethylchlorosilaneand 1.40 g (20.6 mmol) of imidazole. The reaction mixture is evaporatedand the residue is taken up in ethyl acetate, with this solution beingwashed with sat. NaHCO₃ solution, water and saline. The aqueous phasesare extracted 2× with ethyl acetate and the organic phases are driedwith Na₂ SO₄ and evaporated. The residue is dissolved in 30 ml ofmethanol and 7 ml of THF, and this solution is treated with 2.0 g ofpotassium carbonate and 7 ml of water and stirred at RT for 1 h. Thereaction mixture is then partially evaporated and the residue is dilutedwith ice-cold 10% citric acid solution and the whole extracted 3× withethyl acetate. The organic phases are washed with 2 portions of waterand saline, dried with Na₂ SO₄ and evaporated. Medium pressurechromatography (gradient: 0-50% ethyl acetate in hexane) results in thetitle compound: TLC R_(f) (C)=0.56; t_(Ret) (II)=22.1 min.

88d) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(4-biphenylyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

280 mg (0.46 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(4-biphenylyl)methyl!hexanoic acid in 4.44 ml of 0.25 M NMM/CH₃ CN areactivated, under an N₂ atmosphere, with 193 mg (0.51 mmol) of HBTU.After 5 min. 90 mg (0.51 mmol) of H-(L)-Val-N-(2-methoxyethyl)amide(Example 1b)) are added and the mixture is thoroughly stirred at RT for20 h. Working up in an analogy with Example 1c), and digestion of thecrude product in hexane, results in the title compound: TLC R_(f)(D)=0.2; t_(Ret) (II)=22.7 min.

Example 89 5(S)-(Boc-Amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-(4-biphenylyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

Under a protective gas, 1.4 g (1.6 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-benzyloxyphenyl)-2(R)-(4-biphenylyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in 30 mlof DMF are desilylated with 1.0 g (3.2 mmol) of TBAF and, after 20 h,are worked up in analogy with Example 88. Column chromatography (silicagel, methylene chloride→methylene chloride/methanol 9:1) and stirring upin DIPE affords the title compound: t_(Ret) (II)=18.0 min; FAB-MS (M+H)⁺=752.

The starting material is prepared in the following manner:

89a) 5(S)- 1(S)-(Boc-Amino)-2-(p-benzyloxyphenyl)-ethyl!-3(R)-(4-biphenylyl)-methyl!dihydrofuran-2-(3H)-one

In analogy with Example 5d), 5.55 g (13.5 mmol) of 5(S)-1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)ethyl!dihydrofuran-2-(3H)-onepreparation, see Example 1g)!, dissolved in 20 ml of THF and 2.3 ml ofDMPU, are deprotonated, at -70° C., with 27 ml of a 1 M solution oflithium bis(trimethylsilyl)amide in THF, and alkylated (1 h) with 5.0 g(20.2 mmol) of 4-biphenylylmethyl bromide (Salor, Milwaukee, USA) in 16ml of THF. Protonating with 5 ml (67.4 mmol) of propionic acid and 5 mlof water, at -75° C., extracting and medium pressure chromatography(gradient: 30-50% ethyl acetate in toluene) results in the titlecompound: TLC R_(f) (Q)=0.15; t_(Ret) (II)=20.0 min.

89b) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-(4-biphenylylmethyl!hexanoic acid

4.56 g (7.9 mmol) of 5(S)-l(S)-(Boc-amino)-2-(p-benzyloxyphenyl)-ethyl!-3(R)-(4-biphenylyl)methyl!dihydrofuran-2-(3H)-one are hydrolysed, in 80 ml ofdimethoxyethane, with 31.6 ml of a 1 M solution of lithium hydroxide inwater. After 18 h at RT, the dimethoxyethane is evaporated off on a REand the residue is treated with an ice-cold mixture of 43 ml of sat. NH₄Cl solution, 229 ml of 10% citric acid solution and methylene chloride.The aqueous phase is separated off and extracted 2× with methylenechloride. The organic phases are washed with saline, dried with Na₂ SO₄and evaporated. Crystallization from DIPE yields the title compound:t_(Ret) (II)=17.9 min.

89c)5(S)-(Boc-Amino)-4(S)-(tert-butyloxydimethylsilyloxy)-6-(p-benzyloxyphenyl)-2(R)-(4-biphenylyl)methyl!hexanoic acid

3.19 g (5.4 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-(4-biphenylyl)methyl!hexanoic acid in 55 ml of DMF are silylated, at RTfor 20 h and under a protective gas, with 3.71 g (24.6 mmol) oftert-butyldimethylchlorosilane and 3.0 g (44 mmol) of imidazole. Thereaction mixture is evaporated and the residue is taken up in ethylacetate; this solution is then washed with sat. NaCO₃ solution, waterand saline. The aqueous phases are extracted 2× with ethyl acetate andthe organic phases are dried with Na₂ SO₄ arid evaporated. The residueis dissolved in 64 ml of methanol and 15 ml of THF, and this solution istreated with 4.5 g of potassium carbonate and 15 ml of water and stirredat RT for 1 h. Working up in analogy with Example 88c), and mediumpressure chromatography (gradient: 0-10% methanol in methylenechloride), results in the title compound: TLC R_(f) (B)=0.7; t_(Ret)(II)=22.7 min.

89d)5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-benzyloxyphenyl)-2(R)-(4-biphenylyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

1000 mg (1.44 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-benzyloxyphenyl)-2(R)-(4-biphenylyl)methyl!hexanoic acid in 13.8 ml of 0.25 M NMN/CH₃ CN areactivated, under an N₂ atmosphere, with 601 mg (1.58 mmol) of HBTU.After 5 min, a quantity of 276 mg (1.58 mmol) ofH-(L)-Val-N-(2-methoxyethyl)amide (Example 1b) is added and the mixtureis thoroughly stir-red at RT for 20 h. Working up in analogy withExample ic), and medium pressure chromatography (gradient: 40-60% ethylacetate in hexane), results in the title compound: TLC R_(f) (C)=0.33;t_(Ret) (II)=23.5 min.

Example 90 5(S)-(Boc-Amino)-4(S)-hydroxy-6-(p-hydroxyphenyl)-2(R)-(4-biphenylyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

Hydrogenating 200 mg (0.265 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-(4-biphenylyl)methyl!hexanoyl-(L)-Val-N-(2-methoxy-ethyl)amide (Example89) i n 20 ml of methanol/methylene chloride, 1:1, in the presence of0.1 g of 10% Pd/C, filtering off the catalyst and evaporating, affordsthe title compound: t_(Ret) (II)=14.5 min; FAB-MS (M+H)⁺ =662.

Example 91 5(S)-(Boc-Amino)-4(S)-hydroxy-6-(p-methylphenyl)-2(R)-(4-biphenylyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A solution of 173 mg (0.26 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-hydroxyphenyl)-2(R)-(4-biphenylyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide (Example90) in 5 ml of DMF/dioxane, 1:1, is treated, under an N₂ atmosphere andwhile cooling with ice, with 170 mg (0.52 mmol) Of Cs₂ CO₃ and 16 μl(0.26 mmol) of methyl iodide. After the mixture has been stirred at RTfor 20 h, 4.5 ml of ice-water are added and the mixture is finallydiluted with water and methylene chloride. The aqueous phase isseparated off and extracted 2× with methylene chloride. The organicphases are washed with water and saline, dried with Na₂ SO₄ andevaporated. Stirring up the residue in hexane affords the titlecompound: t_(Ret) (II)=16.2 min; FAB-MS (M+H)⁺ =676.

Example 92 5(S)-(Boc-Amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-({2'-cyanobiphenyl}-4-yl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

Under an N₂ atmosphere, 2.11 g (2.36 mmol) of5(S)-(Boc-amino)4(S)-(tert-butyldimethylsilyloxy)-6-(p-benzyloxyphenyl)-2(R)-({2'-cyanobiphenyl}-4-yl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amidein 49 ml of DMF are desilylated with 1.49 g (4.7 mmol) of TBAF and,after 20 h, worked up in analogy with Example 88). Stirring up in hexaneaffords the title compound: t_(Ret) (II)=17.4 min; FAB-MS. (M+H)⁺ =777.

The starting material is prepared in the following manner:

92a) 5(S)- 1(S)-(Boc-Amino)-2-(p-benzyloxyphenyl)ethyl!-3(R)-({2'-cyanobiphenyl}-4-yl)methyl!dihydrofuran-2-(3H)-one

In analogy with Example 5d), 5.00 g (12.1 mmol) of 5(S)-1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)ethyl!dihydrofuran-2-(3H)-onepreparation, see Example 1g)!, dissolved in 22 ml of THF and 2.4 ml ofDMPU, are deprotonated, at -70° C., with 23.5 ml of a 1 M solution oflithium bis(trimethylsilyl)amide in THF, and alkylated (2 h) with 3.43 g(12.1 mmol) of 4-(bromomethyl)-2'-cyanobiphenyl 96%; for preparation,see for example: J. Med. Chem. 34, 2525 (1991)!. Protonating with 4.5 mlof propionic acid and 4.5 ml of water, at -75° C., extracting, columnchromatography (silica gel, hexane/ethyl acetate, 2:1) andrecrystallization from hot ethyl acetate/hexane, results in the titlecompound: TLC R_(f) (D)=0.3; t_(Ret) (II)=19.0 min; FAB-MS (M+H)⁺ =603.

92b) 5(S)-(Boc-Amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-({2'-cyanobiphenyl}-4-yl)methyl!hexanoic acid (lithium salt)

4.59 g (7.6 mmol) of 5(S)-1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)ethyl!-3(R)-({2'-cyanobiphenyl}-4-yl)methyl!dihydrofuran-2-(3H)-one in 120 ml ofdimethoxyethane and 61 ml of water are stirred together with 30 ml of a1 M solution of lithium hydroxide in water, with a white suspensionbeing formed. After 16 h at RT, the crystals are filtered off withsuction and washed with dimethoxethane (→lithium salt of the titlecompound): anal. calc. for C₃₈ H₃₉ N₂ O₆ Li×21H₂ O: C 68.87%, H 6.54%, N4.23%, H₂ O 5.44; found: C 68.4%, 1H 6.5%, N 4.2%, H₂ O 5.23; t_(Ret)(II)=17.2 min; FAB-MS (M+H)⁺ =627. The mother liquor is partiallyevaporated and the residue is treated with an ice-cold mixture of 340 mlof sat. NH₄ Cl solution, 30 ml of 10% citric acid solution and methylenechloride. The aqueous phase is separated off and extracted 2× withmethylene chloride. Washing the organic phases with saline, drying themwith Na₂ SO₄ and evaporating them yields the title compound as a freeacid.

92c)5(S)-(Boc-Amino)-4(S)-(tert-butyloxydimethylsilyloxy)-6-(p-benzyloxyphenyl)-2(R)-({2'-cyanobiphenyl}-4-yl)methyl!hexanoic acid

4.7 g (7.5 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-({2'-cyanobiphenyl}-4-yl)methyl!hexanoic acid (lithium salt) in 8.1 mlof DMF is stirred, at RT for 20 h, together with 5.2 g (34.6 mmol) oftert-butyldimethylchlorosilane and 4.18 g (61.4 mmol) of imidazole whileexcluding moisture. Since HPLC indicates that starting material is stillpresent, a further 1.02 g of imidazole and 1.13 g oftert-butyldimethylchlorosilane are added. After 2 days, the reactionmixture is poured onto ice-water and the whole is extracted 3× withethyl acetate. The organic phases are washed with 10% citric acidsolution, water and saline, dried with Na₂ SO₄ and evaporated. Theresidue is taken up in 91 ml of methanol and 34 ml of THF, and thissolution is treated with 6.2 g of potassium carbonate and 34 ml ofwater, and stirred at RT for 1.5 h. The reaction mixture is subsequentlypartially evaporated and the residue is diluted with ice-cold 10% citricacid solution with the whole then being extracted with 3× ethyl acetate.The organic phases are washed with 2 portions of water and saline, driedwith Na₂ SO₄ and evaporated. Column chromatography (silica gel,hexane/ethyl acetate, 1:1) results in the title compound: TLC R_(f)(C)=0.21; t_(Ret) (II)=22.0 min.

92d)5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-benzyloxyphenyl)-2(R)-({2'-cyanobiphenyl}-4-yl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

2.00 g (2.72 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-benzyloxyphenyl)-2(R)-({2'-cyanobiphenyl}-4-yl)methyl!hexanoic acid, 652 mg (4.83 mmol) ofHOBT, 1.54 g (8.05 mmol) of EDC and 1.17 ml (8.37 mmol) of triethylamineare initially introduced in 24 ml of DMF under an N₂ atmosphere. 674 mg(3.87 mmol) of H-(L)-Val-N-(2-methoxyethyl)amide (Example 1b) are addedto this mixture, and the whole is thoroughly stirred at RT overnight.The reaction mixture is evaporated under HV. The residue is partitionedbetween 3 portions of methylene chloride, 10% citric acid solution, sat. NaHCO₃ solution and saline. Drying the organic phases with Na₂ SO₄,evaporating them, and recrystallizing the residue from hot ethylacetate/hexane, affords the title compound: t_(Ret) (II)=22.7 min;FAB-MS (M+H)⁺ =891.

Example 93 5(S)-(Boc-Amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-({2'-cyanobiphenyl}-4-yl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

Hydrating 1.20 g (1.54 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-({2'-cyanobiphenyl}-4-yl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide(Example 92) in 40 ml of methanol and 15 ml of THF in the presence of0.24 g of 10% Pd/C, filtering off the catalyst, evaporating, andprecipitating with DIPE from a concentrated solution in methanol,affords the title compound: t_(Ret) (II)=13.7 min; FAB-MS (M+H)⁺ =687.

Example 94 5(S)-(Boc-Amino)-4(S)-hydroxy-6-(p-methoxyphenyl)-2(R)-({2'-cyanobiphenyl}-4-yl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A solution of 100 mg (0.145 mmol) of5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-hydroxyphenyl)-2(R)-({2'-cyanobiphenyl}-4-yl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide(Example 93) in 3 ml of DMF/dioxane, 1:1 is treated, under an N₂atmosphere and while being cooled with ice, with 94.6 mg (0.29 mmol) ofCs₂ CO₃ and 9 μl (0.145 mmol) of methyl iodide. After the mixture hasbeen stirred at RT for 20 h, HPLC indicates that starting material isstill present; the same quantities of Cs₂ CO₃ and methyl -in iodide aretherefore added once again and the mixture is stirred over a furthernight. 2.5 ml of ice-water are added to the reaction mixture and thesuspension is diluted with water and methylene chloride. The aqueousphase is separated off and extracted 2× with methylene chloride. Theorganic phases are washed with water and saline, dried with Na₂ SO₄ andevaporated. Column chromatography (silica gel, methylene chloride/THF15:1→4:1) and stirring up the residue in hexane affords the titlecompound: TLC R_(f) (R)=0.1; t_(Ret) (II)=15.5 min; FAB-MS (M+H)⁺ =701.

Example 95 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-ethoxyethyl)amide

1120 mg (1.42 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-ethoxyethyl)amidein 14 ml of abs. DMF are treated with 920 mg (2.84 mmol) of TBAF, andthe reaction mixture is stirred at RT for 21 h under argon. It is thenpoured onto cold saline and the solid is filtered. This solid isdissolved in ethyl acetate and the solution is washed, in succession,with water, sat. sodium bicarbonate solution and saline. The combinedaqueous phases are reextracted with ethyl acetate. The combined organicphases are dried over sodium sulfate and concentrated at approximately30° C. The residue is digested in diisopropyl ether and filtered off.After having been filtered off, the title compound is washed with hexaneand subsequently dried under reduced pressure. m.p.: 117° C. TLC R_(f)(A)=0.28. FAB-MS (M+H)⁺ =674. HPLC t_(Ret) =15.19 min (gradient II); IR(methylene chloride)=inter alia 3431,2967, 1680, 1494, 1467, 1367, 1275and 1166 cm⁻¹ ; ¹ H-NMR (CD₃ OD)=inter alia 7.30-7.10/m (5H); 6.78 and6.61/each d (each 1H); 4.03/d (1H); 3.85, 3.81 and 3.80/each s (each3H); 3.46/q (2H), 1.32 and 1.26/each s (in all 9H from Boc), 1.15/t(3H); 0.82/pseudo t (6H).

The starting material is prepared in the following manner:

95a) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-ethoxyethyl)amide

In analogy with Example 1c), 1.27 g (2.05 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoic acid (Example 47e)) and 460 mgof H-(L)-Val-N-(2-ethoxyethyl)amide in 19.2 ml of 0.25 M NMM/CH₃ CN arereacted with 860 mg of HBTU, within a reaction time of 20 h, to form thetitle compound. The latter is dissolved in ethyl acetate and thissolution is washed, in succession, with 10% cold citric acid, water,saturated sodium bicarbonate solution and saline (2×). After the organicphase has been dried over sodium sulfate, it is filtered andconcentrated under reduced pressure. The title compound is purified bymedium pressure column chromatography (8 bar, methylenechloride/methanol). TLC R_(f) (A)=0.5; FAB-MS (M+H)⁺ =788; IR (methylenechloride)=inter alia 3436, 2932, 1666, 1602, 1495, 1467, 1367, 1249 and1164 cm⁻¹.

95b) H-(L)-Val-N-(2-ethoxyethyl)amide

In analogy with Example 1b), the pure title compound is obtained as anoil, after filtering off the catalyst and evaporating the filtrate, byhydrogenating 6.12 g (19.59 mmol) of Z-(L)-Val-N-(2-ethoxyethyl)amide in120 ml of methanol at RT, under low pressure and in the presence of 0.61g of 10% Pd/C: ¹ H-NMR (200 MHz, CDCl₃): 0.80 and 0.95 (2d, 6H), 1.2 (t,3H), 1.35 (b, 2H), 2.25 (m, 1H), 3.2 (d, 1H), 3.45 (t, 2H), 3.47 (m,4H), 7.5 (b, 1H).

95c) Z-(L)-Val-N-(2-ethoxyethyl)amide

5.025 g (20 mmol) of Z-(L)-valine are dissolved in 20 ml of methylenechloride and this solution is treated, at from -10 to -15° C., with 2.68ml (20.4 mmol) of isobutyl chloroformate (Fluka, Buchs, Switzerland) and22.2 ml (20 mmol) of NMM. After the mixture has been stirred for 15minutes, 2.064 g (23.2 mmol) of 2-ethoxyethylamine (Pfaltz & Bauer,Waterbury, USA) are added under a protective gas. The beige suspensionis warmed to RT and treated with 100 ml of ethyl acetate and 40 ml ofwater. After the organic phase has been separated off, it is washed with40 ml of 1N sodium hydroxide solution and with saline (3×). The solutionis dried over sodium sulfate and subsequently evaporated under HV. Theresidue is digested in hexane and filtered off with suction. The titlecompound, which has thus been obtained, is subjected to further reactionwithout any additional purification. TLC R_(f) (A)=0.4; ¹ H-NMR (200MHz, CDCl₃): 0.95 (2d, 6H), 1.2 (t, 3H), 2.1 (m, 1H), 3.4-3.55 (m, 6H),3.97 (dd, 1H), 5.2 (s, 2H), 5.4 (b, 1H), 6.2 (b, 1H), 7.35 (s, 5H).

Example 96 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(3-methoxypropyl)amide

1.19 g (1.51 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy-6-phenyl-2R)-(2,3,4-trimethoxyphenyl)methyl!-hexanoyl-(L)-Val-N-(3-methoxypropyl)amidein 14.5 ml of abs. DMF are treated with 980 mg (3.02 mmol) of TBAF, andthe reaction mixture is stirred at RT for 22 h under argon. It is thenpoured onto cold saline and the solid is filtered off. This solid isdissolved in ethyl acetate and the solution is washed, in succession,with water, sat. sodium bicarbonate solution and saline. The combinedaqueous phases are reextracted with ethyl acetate. The combined organicphases are dried over sodium sulfate and concentrated at approximately30° C. The residue is digested in diisopropyl ether and filtered off.After having been filtered off, the title compound is dried underreduced pressure. m.p.: 131-132° C.; TLC R_(f) (A)=0.23; FAB-MS (M+H)⁺=674. HPLC t_(Ret) =14.88 min (gradient II). IR (methylenechloride)=inter alia 3430, 2966, 1665, 1494, 1467, 1367, 1275 and 1167cm⁻¹ ; ¹ H-NMR (CD₃ OD)=inter alia 7.30-7.20/m (5H); 6.78 and 6.61/eachd (each 1H); 4.031d (1H); 3.85, 3.81 and 3.80/each s (each 3H); 3.7 (m,1H), 3.53 (m, 1H), 3.39 (t, 2H), 3.29 (s, 3H), 1.32 and 1.26/each s (inall 9H from Boc), 0.85/pseudo t (6H).

The starting material is prepared in the following manner:

96a) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-ethoxyethyl)amide

In analogy with Example 1c), 2.47 g (4 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl) methyl!hexanoic acid (Example 47e)) and 830 mg(4.4 mmol) of H-(L)-Val-N-(3-methoxypropyl)amide in 37.6 ml of 0.25 MNMM/CH₃ CN are reacted with 1.67 g HBTU, with in a reaction time of 22h, to form the title compound. The latter is dissolved in ethyl acetateand this solution is washed, in succession, with 10% cold citric acid,water, saturated sodium bicarbonate solution and saline (2×). After theorganic phase has been dried over sodium sulfate, it is filtered andconcentrated under reduced pressure. The title compound is purified bymedium pressure column chromatography (8 bar, methylenechloride/methanol). TLC R_(f) (A)=0.35; FAB-MS (M+H)⁺ =788; IR(methylene chloride)=inter alia 3436, 2932, 1665, 1602, 1494, 1468,1390, 1367, 1250 and 1165 cm⁻¹.

96b) H-(L)-Val-N-(3-methoxypropyl)amide

In analogy with Example 1b), the pure title compound is obtained as anoil, after filtering off the catalyst and evaporating the filtrate, byhydrogenating 22.26 g (69.044 mmol) ofZ-(L)-Val-N-(3-methoxypropyl)amide in 463.3 ml of methanol at RT, underlow pressure and in the presence of 2.226 g of 10% Pd/C: FAB-MS (M+H)⁺=189; ¹ H-NMR (360 MHz, DMSO-D₆): 0.76 and 0.87 (2d, 6H), 1.6 (b, 2H),1.63 (m, 2H), 1.84 (m, 1H), 2.9 (m, 1H), 3.1 (m, 2H), 3.22 (s, 3H), 3.31(m, 2H), 7.82 (b, 1H).

96c) Z-(L)-Val-N-(3-methoxypropyl)amide

In analogy with Example 1a), 20 g (79.6 mmol) of Z-(L)-valine in 250 mlof CH₃ CN and 20.5 ml of 95% NMM (175.1 mmol) are treated with 9 ml(87.55 mmol) of 3-methoxypropylamine (Fluka, Buchs, Switzerland). 33.2 g(87.55 mmol) of HBTU are added to the thick suspension and the whole isthoroughly stirred at RT for 22 h. The reaction mixture is evaporatedunder HV and the residue is taken up in ethyl acetate, with thissolution being extracted with water, 2×10% citric acid solution, water,2× sat. us NaHCO₃ solution and saline. The aqueous phases are extracteda further 2× with ethyl acetate and the organic phases are dried withNa₂ SO₄ and evaporated. Crystallization from ethyl acetate/hexaneresults in the title compound: TLC R_(f) (G)=0.41; t_(Ret) (II)=11.86min; FAB-MS (M+H)⁺ =323.

Example 97 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(3-ethoxypropyl)amide

0.97 g (1.57 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(3-ethoxypropyl)amidein 11 ml of abs. DMF is treated with 814 mg of TBAF and the reactionmixture is stirred at RT for 18 h under argon. It is then dissolved inethyl acetate and this solution is washed, in succession, with water,sat. sodium bicarbonate solution and saline. The combined aqueous phasesare reextracted with ethyl acetate. The combined organic phases aredried over sodium sulfate and concentrated at approximately 30° C. Theresidue is purified by column chromatography (silica gel, C). TLC R_(f)(A)=0.44; FAB-MS (M+H)⁺ =688; HPLC t_(Ret) =15.43 min (gradient II); ¹H-NMR (CD₃ OD)=inter alia 7.30-7.10/m (5H); 6.78 and 6.61/each d (each1H); 4.0 (d, 1H); 3.85, 3.81 and 3.80/each s (each 3H); 3.7 (m, 1H),3.53 (m, 1H), 3.45 (q, 2H) and (m, 2H), 3.17 (m, 2H), 2.85-2.7 (2m, 5H),1.93-1.6 (m, 5H), 1.32 and 1.26/each s (in all 9H from Boc),0.85/pseudo-t (6H).

The starting material is prepared in the following manner:

97a) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(3-ethoxypropyl)amide

In analogy with Example 1c), 1.235 g (2 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoic acid (Example 47e)) and 445 mg(2.2 mmol) of H-(L)-Val-N-(3-ethoxypropyl)amide in 18.8 ml of 0.25 MNMM/CH₃ CN are reacted with 0.835 g of HBTU, within a reaction time of22 h to form the title compound. After the suspension has beenconcentrated, it is dissolved in ethyl acetate and this solution iswashed, in succession, with 10% cold citric acid, water, saturatedsodium bicarbonate solution and saline (2×). After the organic phase hasbeen dried over sodium sulfate, it is filtered and concentrated underreduced pressure. The title compound is purified by columnchromatography (silica gel, methylene chloride/methanol: 99/1). TLCR_(f) (C)=0.32; t_(Ret) (II)=22.58 min; FAB-MS (M+H)⁺ =802.

97b) H-(L)-Val-N-(3-ethoxypropyl)amide

In analogy with example 1b), the pure title compound is obtained as anoil, after filtering off the catalyst and evaporating the filtrate, byhydrogenating 6.2 g (18.4 mmol) of Z-(L)-Val-N-(3-ethoxypropyl)amide in120 ml of methanol at RT, under low pressure and in the presence of 0.62g of 10% Pd/C: ¹ H-NMR (200 MHz, CDCl₃): 0.8 and 0.97 (2d, 6H), 1.2 (t,3H), 1.3 (b, 2H), 1.8 (m, 2H), 2.25 (m, 1H), 3.2 (d, 1H), 3.38 (m, 2H),3.45 (m, 4H), 7.55 (b, 1H).

97c) Z-(L)-Val-N-(3-ethoxypropyl)amide

5.025 g (20 mmol) of Z-(L)-valine are dissolved in 20 ml of methylenechloride and this solution is treated, at from -10 to -15° C., with 2.68ml (20.4 mmol) of isobutyl chloroformate and 2.2 ml (20 mmol) of NMM.After the mixture has been stirred for 15 minutes, 2.78 ml (23.2 mmol)of 3-ethoxypropylamine are added under a protective gas. The beigesuspension is warmed to RT and treated with 100 ml of ethyl acetate and40 ml of water. After the organic phase has been separated off, it iswashed with 40 ml of 1N sodium hydroxide solution and with saline (3×).The solution is dried over sodium sulfate and then evaporated under HV.The residue is digested in hexane and filtered off with suction. Thetitle compound which is thus obtained is subjected to further reactionwithout any additional purification. TLC R_(f) (C)=0.35; ¹ H-NMR (200MHz, CDCl₃): 0.95 (2d, 6H), 1.2 (t, 3H), 1.75 (m, 2H), 2.1 (m, 1H),3.3-3.55 (m, 7H), 3.93 (dd, 1H), 5.1 (s, 2H), 5.4 (b, 1H), 6.55 (b, 1H),7.35 (s, 5H).

Example 98 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(3-(n-propyloxy)amide

1.4 g (1.71 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(3-(n-propyloxy)propyl)amidein 16 ml of abs. DMF are treated with 1.17 g of TBAF and the reactionmixture is stirred at RT for 18 h under argon. It is then poured ontosaline/ice, and insoluble material is filtered off. The residue isdissolved in ethyl acetate and this solution is washed, in succession,with water, sat. sodium bicarbonate solution and saline. The combinedaqueous phases are reextracted with ethyl acetate. The combined organicphases are dried over sodium sulfate and concentrated at approximately30° C. The residue is crystallized from diisopropyl ether, a littleethyl acetate and hexane. TLC R_(f) (A)=0.53; FAB-MS (M+H)⁺ =702; HPLCT_(Ret) =16.31 min (gradient II); ¹ H-NMR (CD₃ OD)=inter alia 7.30-7.10/(m, 5H); 6.78 and 6.61/each d (each 1H); 4.0 (d, 1H); 3.85, 3.81 and3.80 (each s, each 3H); 3.7 (m, 1H), 3.54 (m, 1H), 3.43 (t, 2H) 3.37 (t,2H), 3.15 (m, 2H), 2.9-2.63 (2m, 5H), 1.93 (m, 1H), 1.82-1.5 (m, 6H),1.32 and 1.26/each s (in all 9H from Boc), 0.85/pseudo t (6H).

The starting material is prepared in the following manner:

98a) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(3-(n-propyloxy)-propyl)amide

In analogy with Example 1c), 1.235 g (2 mmol) of5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoic acid (Example 47e)) and 497 mg(2.3 mmol) of H-(L)-Val-N-(3-(n-propyloxy)propyl)amide in 18.8 ml of0.25 M NMM/CH₃ CN are reacted with 0.835 g of HBTU, within a reactiontime of 22 h, to form the title compound. After the suspension has beenconcentrated, it is dissolved in cold ethyl acetate and this solution iswashed, in succession, with 10% cold citric acid, water, saturatedsodium bicarbonate solution and saline (2×). After the organic phase hasbeen dried over sodium sulfate, it is filtered and concentrated underreduced pressure. The title compound is purified by columnchromatography (silica gel, methylene chloride/methanol: 99/1). TLCR_(f) (C)=0.27; t_(Ret) (II)=23.09 min; FAB-MS (M+H)⁺ =816.

98b) H-(L)-Val-N-(3-(n-propyloxy)propyl)amide

In analogy with Example 1b), the pure title compound is obtained as anoil, after filtering off the catalyst and evaporating the filtrate, byhydrogenating 6.3 g (17.48 mmol) ofZ-(L)-Val-N-(3-(n-propyloxy)propyl)amide in 120 ml of methanol at RT,under low pressure and in the presence of 0.63 g of 10% Pd/C: ¹ H-NMR(200 MHz, CDCl₃): 0.8 (d, 3H), 0.9 and 0.97 (2d, 6H), 1.25 (b, 2H), 1.4(m, 2H), 1.78 (m, 2H), 2.25 (m, 1H), 3.2 (d, 1H), 3.38 (m, 4H), 3.5 (m,2H), 7.5 (b, 1H).

98c) Z-(L)-Val-N-(3-(n-propyloxy)propyl)amide

5.025 g (20 mmol) of Z-(L)-valine are dissolved in 20 ml of methylenechloride and this solution is treated, at from -10 to -15° C., with 2.68ml (20.4 mmol) of isobutyl chloroformate and 2.2 ml (20 mmol) of NMM.After the mixture has been stirred for 15 min, 2.72 ml (23.2 mmol) of3-(n-propyloxy)propylamine (Tokyo Kasei Organic Chemicals, Tokyo, Japan)are added under a protective gas. The beige suspension is warmed to RTand treated with 100 ml of ethyl acetate and 40 ml of water. After theorganic phase has been separated off, it is washed with 40 ml of 1Nsodium hydroxide solution and with saline (3×). The solution is driedover sodium sulfate and then evaporated under HV. The residue isdigested in hexane and filtered off with suction. The title compoundwhich is thereby obtained is subjected to further reaction without anyadditional purification. TLC R_(f) (C)=0.6; ¹ H-NMR (200 MHz, CDCl₃):0.92 (m, 9H), 1.6 (m, 2H), 1.75 (m, 2H), 2.1 (m, 1H), 3.35 (m, 4H), 3.5(m, 2H), 3.93 (dd, 1H), 5.1 (s, 2H), 5.4 (b, 1H), 6.5 (b, 1H), 7.35 (s,5H).

Example 995(S)-(3-Hydroxy-2-methylphenylcarboxyamino)-4(S)-hydroxy-6-(p-methoxyphenyl)-2(R)-({2'-cyanobiphenyl}-4-yl)methyl!hexanoyl-(L)-Val-N-(2-(methoxyethyl)amide

The title compound is prepared in analogy with one of the methodsdescribed in the abovementioned examples.

Example 100 5(S)-(Boc-Amino)-4(S)-hydroxy-6-phenyl-2(R)-({2'-cyanobiphenyl}-4-yl)methyl!hexanoyl-(L)-Val-N-(2-(methoxyethyl)amide

The title compound is prepared in analogy with one of the methodsdescribed in the abovementioned examples.

Example 101 5(S)-(Boc-Amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-({2'-cyanobiphenyl}-4-yl)methyl!hexanoyl-(L)-Val-N-(2-(methoxyethyl)amide

The title compound is prepared in analogy with one of the methodsdescribed in the abovementioned examples.

Example 1025(S)-(p-Nitrobenzenesulfonoylamino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-(methoxyethyl)amide

1.00 g (1.67 mmol) of 5(S)-amino-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide(hydrochloride salt) (Example 83a)) is dissolved in dichloromethane, andthe organic phase is washed with sat. sodium bicarbonate solution, driedover sodium sulfate and concentrated. The liberated amine is stirred, at0° C. for 17 h, in 25 ml of pyridine together with 475 mg (1.25equivalents) of 4-nitrobenzenesulfonyl chloride (Fluka, Buchs,Switzerland). After a further 285 mg (0.75 equivalents) of4-nitrobenzenesulfonyl chloride have been added, the mixture is allowedto continue reacting at RT for a further 3 h. The reaction mixture isconcentrated. The oily residue is taken up in cold ethyl acetate andthis solution is washed, in succession, with 10% citric acid solution,saline, sat. sodium bicarbonate solution and saline. After drying oversodium sulfate, the solvent is removed. The resulting crystallineresidue is crystallized from ethyl acetate/hexane, filtered off withsuction, washed with hexane and dried, with the title compound beingobtained: FAB-MS (M+H)⁺ =745; m.p.: 195-198° C.; t_(Ret) (II)=10.45 min.

Example 1035(S)-(p-Aminobenzenesulfonoylamino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenylmethyl!hexanoyl-(L)-Val-N-(2-(methoxyethyl)amide

200 mg (0.268 mmol) of5(S)-(p-nitrobenzenesulfonylamino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide(Example 102) are dissolved in 6 ml of methanol and 1 equivalent ofacetic acid. After the addition of 50 mg of Raney nickel (in ethanol),the mixture is hydrogenated at RT and under standard pressure. Afterhydrogenation is complete, the reaction solution is separated offthrough ®Hyflo Super Cel (filtering aid based on kieselguhr(diatomaceous earth); Fluka, Buchs, Switzerland). The solution isconcentrated. The resulting crystalline residue is recrystallized frommethanol/hexane. The title compound is obtained after filtering off theresidue and washing it with hexane: FAB -MS (M+H)⁺ =715; m.p.: 200-206°C.; t_(Ret) (II)=9.14 min.

Example 104 5(S)-(o-Methyl-p-nitrobenzenesulfonoyl)amino!-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-(methoxyethyl)amide

The title compound is prepared in analogy with one of the methodsdescribed in the abovementioned examples.

Example 105 5(S)-(o-Methyl-p-aminobenzenesulfonoyl)amino!-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)methyl!hexanoyl-(L)-Val-N-(2-(methoxyethyl)amide

The title compound is prepared in analogy with one of the methodsdescribed in the abovementioned examples.

Example 106 Capsules (I)

Crystalline5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenylmethyl)-hexanoyl-(L)-Val-N-(2-methoxy-ethyl)amide(active substance) is micronized (particle size, from approximately 1 to100 μm) with a customary knife mixer (for example Turmix). ®Pluronic F68 (block polymer consisting of polyethylene and polypropylene glycol;Wyandotte Chem. Corp., Michigan, USA; also obtainable from Emkalyx,France; BASF trademark) is likewise micronized with a customary mixer,and the fine fraction is separated by screening using a sieve (0.5 mm)and subjected to further use as described below. 16.00 g of sesame oilare initially introduced in a beaker, and 1.20 g of the micronizedactive substance, 1.20 g of the fine fraction of ®Pluronic F 68 and 1.20g of hydroxypropyl methyl cellulose (HP-M-603 cellulose from Shin-EtsuChemicals Ltd., Tokyo, Japan) are added while stirring with an agitator(IKA-Werk, FRG) which is combined with a cogged stirrer (diameter: 46mm) (stirring speed: 2000 rpm). 20 min of stirring at the given stirringspeed produces a suspension of a pasty consistency which is used to fillhard gelatin capsules (20×40 mm; R. P. Scherer AG, Eberbach, FRG).

Example 107 Capsules (II)

The following constituents are processed as follows in order to prepare10,000 capsules containing 100 mg of active compound (for example5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenylmethyl)-hexanoyl-(L)-Val-N-(2-methoxyethyl)amide) percapsule:

    ______________________________________    Active compound          1000 g    ® Pluronic F 68      1000 g    Hydroxypropyl methyl cellulose                             1000 g    Sesame oil               1000 g    ______________________________________     (origin of the constituents: see Example 106)

The sesame oil is initially introduced in a heatable vessel (Fryma), andthe Pluronic F 68 is sprinkled in. The vessel is heated to 60° C. andthe Pluronic F 68 is distributed by stirring the mixture (durationapproximately 2 h). The mixture is cooled down to approximately 30° C.while being stirred and homogenized. The hydroxypropyl methyl celluloseand the active compound are sprinkled in and distributed in the oilymass while stirring and homogenizing (approximately 1 h). Thesuspension, which is of a pasty consistency, is used to fill hardgelatin capsules (size 0; obtainable, for example, from Elanco orParke-Davies (Caprogel)) or soft gelatin capsules (20 mm oblong; R.P.Scherer AG, Eberbach, FRG) with the aid of the customary equipment.

Example 108 Gelatin Solution

An aqueous solution, which has been sterilized by filtration and whichcontains, as active compound, one of the compounds of the formula Imentioned in the preceding examples, together with 20% cyclodextrins assolubilizers, is mixed, under aseptic conditions and while heating, witha sterile gelatin solution, which contains phenol as preservative, suchthat 1.0 ml of solution has the following composition:

    ______________________________________    Active compound         3           mg    Gelatin                 150.0       mg    Phenol                  4.7         mg    Dist. water containing 20% cyclodextrins                            1.0         ml    as solubilizers    ______________________________________

Example 108 Sterile Dry Substance for Injection

5 mg of one of the compounds of the formula I mentioned in the precedingexamples, as active compound, are dissolved in 1 ml of an aqueoussolution containing 20 mg of mannitol and 20% cyclodextrins assolubilizers. The solution is sterilized by filtration and used, underaseptic conditions, to fill a 2 ml ampoule, after which it is frozen andlyophilized. Before use, the lyophilisate is dissolved in 1 ml ofdistilled water or 1 ml of physiological sodium chloride solution. Thesolution is used for intramuscular or intravenous administration. Thisformulation can also be used to fill double-chambered disposablesyringes.

Example 109 Nasal Spray

500 mg of a finely ground (<5.0 μm) powder of one of the compounds ofthe formula I mentioned in the preceding examples, as active compound,are suspended in a mixture of 3.5 ml of Myglyol 812® and 0.08 g ofbenzyl alcohol. This suspension is introduced into a containerpossessing a dosing valve. 5.0 g of Freon 12®, which is under pressuredue to the valve, are introduced into the container. The "Freon" isdissolved in the Myglyol/benzyl alcohol mixture by shaking. This spraycontainer contains approximately 100 individual doses which can beadministered individually.

Example 110 Lacquered Tablets

The following constituents are processed for preparing 10,000 tabletseach containing 100 mg of active compound:

    ______________________________________    Active compound       1000 g    Corn starch           680 g    Colloidal silicic acid                          200 g    Magnesium stearate    20 g    Stearic acid          50 g    Sodium carboxymethyl starch                          250 g    Water                 quantum satis    ______________________________________

A mixture of one of the compounds of the formula I mentioned in thepreceding examples, as active compound, 50 g of corn starch and thecolloidal silicic acid is processed together with starch pasteconsisting of 250 g of corn starch and 2.2 kg of demineralized water toform a moist mass. This is forced through a sieve of 3 mm mesh size anddried in a fluidized-bed dryer at 45° for 30 min. The dried granulate ispressed through a sieve of 1 mm mesh size, mixed with a previouslyscreened mixture (1 mm sieve) of 330 g of corn starch, the magnesiumstearate, the stearic acid and the sodium carboxymethyl starch, andpressed into slightly domed tablets.

Example 111 Pharmacokinetics in the Dog

Formulation: Capsules from Example 106

Conduct of the experiment: 2 female beagle breeding dogs (Ciba Geigy,Sisseln) are used. During the experiment, the bitches have free accessto water and are given their last meal approximately 16 h before thebeginning of the experiment. Feed is proffered once again at 8 h afterthe beginning of the experiment. Each bitch is given 2 capsules of thespecified formulation, which capsules together contain 1.2 g of5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenylmethyl)hexanoyl-(L)-Val-N-(2-methoxyethyl)amide(active substance), corresponding to an average dose of approximately100 mg/kg of body weight. Blood from the saphenous vein is collected inheparinized tubes at different times after the administration.

In order to analyse the plasma concentration, the heparinized blood iscentrifuged (4000×g, 20 min) and the plasma is removed and mixed with anequal volume of acetonitrile. The mixture is kept on ice for 30 min. Theprotein precipitate is removed by centrifugation (10,000×g, 5 min) andthe supernatant is centrifuged once again. The concentration of theactive substance in the final supernatant which is obtained isdetermined by means of reversed-phase HPLC: the HPLC analysis is carriedout on an analytical 125×4.6 mm Nucleosil C18 (5 μm) column (Macherey &Nagel, Duren, FRG), which is equilibrated with a mobile phase of 50%acetonitrile and 0.1% trifluoroacetic acid in water. The flow rate is 1ml/min. Under these conditions, the detection limit is 0.1 μM. Theactive substance is detected by UV absorption at 215 nm. Theconcentrations are determined by the external standard method; theheights of the peaks are used to determine the concentrations bycomparison with standard curves. The standard curves are obtained byHPLC analysis of dog plasmas containing known added concentrations ofthe active substance, which plasmas are themselves worked up in a manneranalogous to that for the samples, by means of the abovementioned steps.

                  TABLE OF VALUES    ______________________________________    Results:    Time (h)           Bitch 1 Bitch 2    ______________________________________     2                 7592    13947     4                 4688    4570     6                 616     192     8                 44      18    12                 11      <0.1    24                 14      <0.1    Area under the curve                       26101   37473    (AUC) for the period    from 0 to 24 h    (ng × h/ml)    ______________________________________     The values are given in ng/ml

Example 112 Synergistic Effect Produced by Combining5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide(Compound from Example 47) with Indinavir or Saquinavir in theExperiment using Cell Lines

The activities of the individual compounds, and the combinations,mentioned in the title, in the coculture of the CEM-SS cell line and thepermanently infected cell line H9/HIV-1/IIIB are determined using themethod described above in association with the description of thepharmacological properties. The measurement result is expressed as %reduction of the reverse transcriptase (RT) activity. The results arepresented in the following table; measurement results which confirm theoccurrence of synergism are emphasized by underlining:

    ______________________________________    a) Combination with saquinavir:    Concentration of the    active compound                  % Inhibition of the RT activity by    Example 47        Example 47        Combination of    title compound             Saquinavir                      title compound                                 Saquinavir                                        Example 47    (nM)     (nM)     alone      alone  and Saquinavir    ______________________________________    3.125    0.78     2.7%       6.6%   24.2%             1.56     --         14.7%  23.7%             3.125    --         39.3%  83.7%    6.25     1.56     1.3%       14.7%  58.0%             3.125    --         39.3%  90.5%             6.26     --         93.8%  96.6%    ______________________________________

    ______________________________________    b) Combination with indinavir:    Concentration of the    active compound                  % Inhibition of the RT activity by    Example 47        Example 47        Combination of    title compound             Indinavir                      title compound                                 Indinavir                                        Example 47    (nM)     (nM)     alone      alone  and Indinavir    ______________________________________    6.25     12.5     1.3%       3.2%   39.1%    12.5     12.5     52.0%      3.2%   76.6%             25       --         59.7%  90.7%    ______________________________________

Consequently, an additive to synergistic effect can be seen incoculture.

Example 113 Synergistic Effect Produced by Combining5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)-methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide(Compound from Example 47) with Indinavir or Saquinavir in theExperiment using Peripheral Mononuclear Blood Cells

The activities of the individual compounds, and the combinations,specified in the title, in the peripheral mononuclear blood cell cultureare determined using the method described above in association with thedescription of the pharmacological properties. The measurement result isexpressed as the cumulative activity of the reverse transcriptase (RT),in cpm/1.25 μl (number of measured ³² p disintegrations per 1.25 μl oftest mixture and minute) on day 17 after the infection. The results arepresented in the following table; measurement results which confirm theoccurrence of synergism are emphasized by underlying. The testcompound(s) is/are re-added in associated with each change of the mediumon days 0, 3, 6, 10 and 13):

    ______________________________________    Cumulative RT activity (cpm/μl) on day 17 after the infection    Concentration of the    title compound                Concentration of saquinavir (nM)    from Example 47                0      7.5     15    30    60  120    ______________________________________    0           7505   9411    10299 111   64  47    7.5         7909   8724    541   57    64  57    15          9132   5381    120   61    58  50    30          8457   255     63    51    59  53    60          1823   91      59    45    57  43    120         49     60      50    70    63  63    ______________________________________

Consequently, a synergistic effect can also be detected in theexperiment using human peripheral mononuclear blood cells.

What is claimed is:
 1. A compound of the formula ##STR55## wherein R₁ islower alkoxycarbonyl;R₂ is phenyl substituted by one or more radicalsindependently selected from lower alkyl, hydroxy, lower alkoxy, loweralkoxy-lower alkoxy or phenyl-lower alkoxy; R₃ is phenyl substituted bypyridyl lower alkoxy in which pyridyl is bonded via a ring carbon atom;R₄ is lower alkyl; R₅ is lower alkyl;and n is 1 or 2; or a salt thereof,provided at least one salt-forming group is present.
 2. A compound ofthe formula I according to claim 1,in which R₁ is lower-alkoxycarbonyl;R₂ is phenyl which is substituted by one or more radicals which areselected, independently of each other, from lower alkyl, hydroxy, loweralkoxy, phenyl-lower-alkoxy and lower ,alkoxy-lower alkoxy; R₄ is loweralkyl; R₅ is lower alkyl; and n is 1 or 2; or a salt thereof, providedat least one salt-forming group is present.
 3. A compound of the formulaI according to claim 1, whereinR₁ is lower-alkoxycarbonyl; R₂ and R₃ arepresent in the following combinations; R₂ is 4-(lower alkoxy-loweralkoxy)phenyl and R₃ is 4-(phenyl-pyridyl lower alkoxy); R₄ is loweralkyl; R₅ is lower alkyl; and n is 1 or 2; or a salt thereof, providedat least one salt-forming group is present.
 4. A compound of the formulaI according to claim 1, in whichR₁ is selected from the group consistingof ethoxycarbonyl and tert-butoxycarbonyl; R₂ is selected from4-(benzyloxy)-phenyl, 2-, 3- or 4-methoxyphenyl, 4-isobutyloxyphenyl,trimethoxyphenyl, 4-(2methoxyethoxy)phenyl, 4-methoxy-2-hydroxyphenyl,4-methoxy-2,3-dimethylphenyl, 4-hydroxyphenyl and dimethoxyphenyl; R₄ isisopropyl; R₅ is methyl, ethyl or n-propyl; and n is 1 or 2; or a saltthereof, provided at least one salt-forming group is present.
 5. Acompound of the formula I according to claim 1, in whichR₁ istert-butoxycarbonyl; R₂ is selected from 4-(benzyloxy)-phenyl, 2-, 3- or4-methoxyphenyl, 4-isobutyloxyphenyl, trimethoxyphenyl,4-(2-methoxyethoxy)phenyl, 4-methoxy-2-hydroxyphenyl,4-methoxy-2,3-dimethylphenyl, 4-hydroxyphenyl and dimethoxyphenyl; R₄ isisopropyl; R₅ is methyl or ethyl; and n is 1 or 2; or a salt thereof,provided at least one salt-forming group is present.
 6. A compound ofthe formula I according to claim 1, in whichR₁ is lower-alkoxycarbonyl;R₂ is 4-(lower alkoxy-lower alkoxy)phenyl; R₄ is isopropyl; R₅ ismethyl; and n is
 1. 7. A compound according to claim 1, which is of theformula I', which comes under formula I, ##STR56## in which the radicalshave the meanings specified in each case for compounds of the formula I.8. A compound of the formula I according to claim 7 which is5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-(3-pyridylmethoxy)-phenyl)methyl!hexanoyl-(L)-Val-N-(2-methoxyethyl)amide.9. A pharmaceutical preparation which is appropriate for the treatmentof a disease that is caused by a retrovirus, said preparation comprisingan amount of a compound of formula I according to claim 1 that is activeagainst a retroviral disease, or a pharmaceutically acceptable saltthereof, and at least one pharmaceutically acceptable carrier material.10. A method for treating diseases caused by retroviruses, where acombination, which is therapeutically effective against retroviraldiseases, of a) a compound of the formula I according to claim 1, and b)a further compound, or two or more thereof, which is effective againstretroviruses is administered to a mammal in a quantity which istherapeutically effective against retroviral diseases in order to treata retroviral disease.